103 results on '"Rerks-Ngarm, S"'
Search Results
2. Antibody-dependent cellular cytotoxicity-mediating antibodies from an HIV-1 vaccine efficacy trial preferentially use the VH1 gene family
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Bonsignori M, Pollara J, Moody MA, Kepler TB, Chen X, Gurley TC, Kozink DM, Marshall DJ, Whitesides JF, Kaewkungwal J, Nitayaphan S, Pitisuttithum P, Rerks-Ngarm S, Kim JH, Michael NL, Montefiori DC, Liao H, Ferrari G, and Haynes BF
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Immunologic diseases. Allergy ,RC581-607 - Published
- 2012
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3. V1/V2-directed antibodies elicited in RV144 vaccinees bind to a structurally polymorphic site
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McLellan JS, Gorman J, Bonsignori M, Hwang K, Liao H, Rerks-Ngarm S, Nitayaphan S, Michael NL, Kim JH, Haynes BF, and Kwong PD
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Immunologic diseases. Allergy ,RC581-607 - Published
- 2012
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4. Vector induced skewing of antibody Fc-effector functions
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Chung A, Dugast A, Robinson H, Chan Y, Ackerman ME, Cox J, Koff W, Barouch D, Rerks-Ngarm S, Michael N, Kim J, and Alter G
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Immunologic diseases. Allergy ,RC581-607 - Published
- 2012
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5. Design of an HIV Env antigen that binds with high affinity to antibodies against linear, conformational and broadly neutralizing epitopes within V1/V2
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Liao L, Bonsignori M, Hwang K, Moody AM, Park R, Crawford S, Chen H, Jeffries TL, Cooper M, Lu X, De R, Karasavvas N, Rerks-Ngarm S, Nitayaphan S, Kaewkungwal J, Tovanabutra S, Pitisuttithum P, Tartaglia J, Sinangil F, Kim J, Michael NL, Tomaras GD, Yang Z, Dai K, Pancera M, Nabel GJ, Mascola JR, Kwong PD, Pinter A, Zolla-Pazner S, Alam MS, and Haynes BF
- Subjects
Immunologic diseases. Allergy ,RC581-607 - Published
- 2012
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6. Vaccine-induced ADCC-mediating antibodies target unique and overlapping envelope epitopes
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Pollara J, Bonsignori M, Moody M, Alam M, Liao H, Hwang K, Pickeral J, Kappes J, Ochsenbauer C, Soderberg K, Gurley TC, Kozink DM, Marshall DJ, Whitesides JF, Montefiori D, Robinson JE, Kaewkungwal J, Nitayaphan S, Pitisuttithum P, Rerks-Ngarm S, Kim J, Michael N, Tomaras G, Haynes BF, and Ferrari G
- Subjects
Immunologic diseases. Allergy ,RC581-607 - Published
- 2012
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7. Antibody responses to V2 loop are induced by CRF01_A E and not Clade B envelopes
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Karasavvas N, Karnasuta C, Madnote S, Arworn D, Sinangil F, Rerks-Ngarm S, O'Connell RJ, Nitayaphan S, Ngauy V, Kim JH, Michael NL, and de Souza MS
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Immunologic diseases. Allergy ,RC581-607 - Published
- 2012
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8. T-cell based sieve analysis ties HLA A*02 to vaccine efficacy and IgA-C1 immune correlate in RV144 Thai trial
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Hertz T, Gartland A, Janes H, Li S, Fong Y, Tomaras GD, Morris D, Geraghty D, Kijak GH, Edlefsen PT, Rolland M, Larsen BB, Tovanabutra S, Sanders-Buell E, DeCamp AC, Magaret CA, Ahmed H, Nariya S, Wong K, Zhao H, Deng W, Maust BS, Bose M, Howell S, Lazzaro M, Bates A, Lei E, Bradfield A, Ibitamuno G, Assawadarachai V, O'Connel RJ, deSouza MS, Nitayaphan S, Rerks-Ngarm S, Robb ML, McElrath MJ, Haynes BF, Michael NL, Gilbert PB, Mullins JI, and Kim JH
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Immunologic diseases. Allergy ,RC581-607 - Published
- 2012
- Full Text
- View/download PDF
9. OA04-06 LB. Post-infection cellular immune responses in recipients following ALVAC-HIV® + AIDSVAX® B/E prime-boost vaccination in the Thai Phase III Trial
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Chiu J, Michael NL, Pitsuttihum P, Nitayaphan S, Sukwit S, Eamsila C, Ratto-Kim S, Chantakulkij S, Kaewkungwal J, Trichavaroj R, Kamasuta C, Kim JH, Rerks-Ngarm S, de Souza MS, and Paris RM
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Immunologic diseases. Allergy ,RC581-607 - Published
- 2009
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10. P14-05. Recruitment, retention and participation impact events among women participating in phase III community trial in Thailand
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Benenson MW, Suntharasamai P, Kunasol P, Khamboonruang C, Nitayaphan S, Kaewkungwal J, Rerks-Ngarm S, Pitisuttithum P, and Kim JH
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Immunologic diseases. Allergy ,RC581-607 - Published
- 2009
- Full Text
- View/download PDF
11. Machine Learning Methods Enable Predictive Modeling of Antibody Feature: Function Relationships in RV144 Vaccinees
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Kepler, TB, Choi, I, Chung, AW, Suscovich, TJ, Rerks-Ngarm, S, Pitisuttithum, P, Nitayaphan, S, Kaewkungwal, J, O'Connell, RJ, Francis, D, Robb, ML, Michael, NL, Kim, JH, Alter, G, Ackerman, ME, Bailey-Kellogg, C, Kepler, TB, Choi, I, Chung, AW, Suscovich, TJ, Rerks-Ngarm, S, Pitisuttithum, P, Nitayaphan, S, Kaewkungwal, J, O'Connell, RJ, Francis, D, Robb, ML, Michael, NL, Kim, JH, Alter, G, Ackerman, ME, and Bailey-Kellogg, C
- Abstract
The adaptive immune response to vaccination or infection can lead to the production of specific antibodies to neutralize the pathogen or recruit innate immune effector cells for help. The non-neutralizing role of antibodies in stimulating effector cell responses may have been a key mechanism of the protection observed in the RV144 HIV vaccine trial. In an extensive investigation of a rich set of data collected from RV144 vaccine recipients, we here employ machine learning methods to identify and model associations between antibody features (IgG subclass and antigen specificity) and effector function activities (antibody dependent cellular phagocytosis, cellular cytotoxicity, and cytokine release). We demonstrate via cross-validation that classification and regression approaches can effectively use the antibody features to robustly predict qualitative and quantitative functional outcomes. This integration of antibody feature and function data within a machine learning framework provides a new, objective approach to discovering and assessing multivariate immune correlates.
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- 2015
12. HIV-specific antibody-dependent phagocytosis matures during HIV infection
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Ana-Sosa-Batiz, F, Johnston, APR, Liu, H, Center, RJ, Rerks-Ngarm, S, Pitisuttithum, P, Nitayaphan, S, Kaewkungwal, J, Kim, JH, Michael, NL, Kelleher, AD, Stratov, I, Kent, SJ, Kramski, M, Ana-Sosa-Batiz, F, Johnston, APR, Liu, H, Center, RJ, Rerks-Ngarm, S, Pitisuttithum, P, Nitayaphan, S, Kaewkungwal, J, Kim, JH, Michael, NL, Kelleher, AD, Stratov, I, Kent, SJ, and Kramski, M
- Abstract
Antibody-dependent phagocytosis (ADP) is a potentially important immune mechanism to clear HIV. How HIV-specific ADP responses mature during HIV infection or in response to vaccinations administered, including the partially successful RV144 HIV vaccine, is not known. We established a modified ADP assay to measure internalisation of HIV antibody (Ab)-opsonised targets using a specific hybridisation internalisation probe. Labelled beads were coated with both biotinylated HIV gp140 envelope protein and a fluorescent internalisation probe, opsonised with Abs and incubated with a monocytic cell line. The fluorescence derived from the fluorescent internalisation probe on surface-bound beads, but not from internalised beads, was quenched by the addition of a complementary quencher probe. HIV Env-specific ADP was measured in 31 subjects during primary infection and early chronic HIV infection. Although ADP responses were present early during HIV infection, a significant increase in ADP responses in all 31 subjects studied was detected (P<0.001). However, when we tested 30 HIV-negative human subjects immunised with the Canarypox/gp120 vaccine regimen (subjects from the RV144 trial) we did not detect HIV-specific ADP activity. In conclusion, a modified assay was developed to measure HIV-specific ADP. Enhanced ADP responses early in the course of HIV infection were observed but no ADP activity was detected following the vaccinations administered in the RV144 trial. Improved vaccine regimens may be needed to capitalise on ADP-mediated immunity against HIV.
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- 2014
13. AIDS Vaccine for Asia Network (AVAN): Expanding the Regional Role in Developing HIV Vaccines
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Kent, SJ, Cooper, DA, Vun, MC, Shao, Y, Zhang, L, Ganguly, N, Bela, B, Tamashiro, H, Ditangco, R, Rerks-Ngarm, S, Pitisuttithum, P, Nguyen, VK, Bernstein, A, Osmanov, S, Kent, SJ, Cooper, DA, Vun, MC, Shao, Y, Zhang, L, Ganguly, N, Bela, B, Tamashiro, H, Ditangco, R, Rerks-Ngarm, S, Pitisuttithum, P, Nguyen, VK, Bernstein, A, and Osmanov, S
- Abstract
The HIV/AIDS pandemic continues to spread and an AIDS vaccine is urgently needed. Regional alliances and international collaborations can foster the development and evaluation of the next generation of AIDS vaccine candidates. The importance of coordinating and harmonizing efforts across regional alliances has become abundantly clear. We recently formed the AIDS Vaccine for Asia Network (AVAN) to help facilitate the development of a regional AIDS vaccine strategy that accelerates research and development of an AIDS vaccine through government advocacy, improved coordination, and harmonization of research; develops clinical trial and manufacturing capacity; supports ethical and regulatory frameworks; and ensures community participation.
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- 2010
14. A reply to the letter to the editor by Makela, Herva and Nohynek in response to the article by Rerks-Ngarm S, Treleaven SC, Chunsuttiwat S, Muangchana C, Jolley D, Brooks A, Dejsirilert S, Warintrawat S, Guiver M, Kunasol P, Maynard JE, Biggs B-A, Steinhoff M. Prospective population-based incidence of Haemophilus influenzae type b meningitis in Thailand. Vaccine 2004; 22 : 975-83
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Treleaven, S, Biggs, BA, Steinhoff, M, Rerks-Ngarm, S, Treleaven, S, Biggs, BA, Steinhoff, M, and Rerks-Ngarm, S
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- 2005
15. Prospective population-based incidence of Haemophilus influenzae type b meningitis in Thailand
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Rerks-Ngarm, S, Treleaven, SC, Chunsuttiwat, S, Muangchana, C, Jolley, D, Brooks, A, Dejsirilert, S, Warintrawat, S, Guiver, M, Kunasol, P, Maynard, JE, Biggs, BA, Steinhoff, M, Rerks-Ngarm, S, Treleaven, SC, Chunsuttiwat, S, Muangchana, C, Jolley, D, Brooks, A, Dejsirilert, S, Warintrawat, S, Guiver, M, Kunasol, P, Maynard, JE, Biggs, BA, and Steinhoff, M
- Abstract
There are limited prospective data for Haemophilus influenzae type b (Hib) disease in Asia, where some countries are considering vaccine introduction. A prospective population-based study was conducted to measure the incidence of Hib meningitis in children in two northern provinces of Thailand. Children <5 years with symptoms consistent with bacterial meningitis were enrolled in the study if inclusion criteria were met. The study enrolled 598 children with clinical meningitis, 76% of whom received lumbar puncture. The rate of probable bacterial meningitis was 26.6/100,000 children <5 years per year. There were four cases of laboratory confirmed Hib meningitis (rate 3.8/100,000 children <5 years per year). These findings suggest a relatively low incidence of Hib meningitis. However, additional data from studies of pneumonia are needed to define the Hib disease burden in Thailand.
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- 2004
16. OA04-06 LB. Post-infection cellular immune responses in recipients following ALVAC-HIV® + AIDSVAX® B/E prime-boost vaccination in the Thai Phase III Trial
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Kim, JH, primary, Kamasuta, C, additional, Trichavaroj, R, additional, Kaewkungwal, J, additional, Chantakulkij, S, additional, Ratto-Kim, S, additional, Eamsila, C, additional, Sukwit, S, additional, Nitayaphan, S, additional, Pitsuttihum, P, additional, Michael, NL, additional, Chiu, J, additional, Rerks-Ngarm, S, additional, de Souza, MS, additional, and Paris, RM, additional
- Published
- 2009
- Full Text
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17. P14-05. Recruitment, retention and participation impact events among women participating in phase III community trial in Thailand
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Pitisuttithum, P, primary, Rerks-Ngarm, S, additional, Kaewkungwal, J, additional, Nitayaphan, S, additional, Khamboonruang, C, additional, Kunasol, P, additional, Suntharasamai, P, additional, Benenson, MW, additional, and Kim, JH, additional
- Published
- 2009
- Full Text
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18. Antibody responses to V2 loop are induced by CRF01A E and not Clade B envelopes.
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Karasawas, N., Karnasuta, C., Arworn, D., Sinangil, F., Kim, J. H., de Souza, M. S., Karasavvas, N., Michael, N. L., O'Connel, R. J., Nitayaphan, S., Rerks-Ngarm, S., Madnote, S., and Ngauy, V.
- Subjects
IMMUNOGLOBULINS - Abstract
An abstract of the research paper "Antibody responses to V2 loop are induced by CRF01_A E and not Clade B envelopes," by N. Karasawas and colleagues is presented.
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- 2012
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19. Viral vector delivered immunogen focuses HIV-1 antibody specificity and increases durability of the circulating antibody recall response.
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Williams LD, Shen X, Sawant SS, Akapirat S, Dahora LC, Tay MZ, Stanfield-Oakley S, Wills S, Goodman D, Tenney D, Spreng RL, Zhang L, Yates NL, Montefiori DC, Eller MA, Easterhoff D, Hope TJ, Rerks-Ngarm S, Pittisuttithum P, Nitayaphan S, Excler JL, Kim JH, Michael NL, Robb ML, O'Connell RJ, Karasavvas N, Vasan S, Ferrari G, and Tomaras GD
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- Humans, Antibody Formation, Immunization, Secondary methods, Antibody Specificity, HIV Antibodies, HIV Envelope Protein gp120, HIV-1, HIV Infections prevention & control, AIDS Vaccines, HIV Seropositivity
- Abstract
The modestly efficacious HIV-1 vaccine regimen (RV144) conferred 31% vaccine efficacy at 3 years following the four-shot immunization series, coupled with rapid waning of putative immune correlates of decreased infection risk. New strategies to increase magnitude and durability of protective immunity are critically needed. The RV305 HIV-1 clinical trial evaluated the immunological impact of a follow-up boost of HIV-1-uninfected RV144 recipients after 6-8 years with RV144 immunogens (ALVAC-HIV alone, AIDSVAX B/E gp120 alone, or ALVAC-HIV + AIDSVAX B/E gp120). Previous reports demonstrated that this regimen elicited higher binding, antibody Fc function, and cellular responses than the primary RV144 regimen. However, the impact of the canarypox viral vector in driving antibody specificity, breadth, durability and function is unknown. We performed a follow-up analysis of humoral responses elicited in RV305 to determine the impact of the different booster immunogens on HIV-1 epitope specificity, antibody subclass, isotype, and Fc effector functions. Importantly, we observed that the ALVAC vaccine component directly contributed to improved breadth, function, and durability of vaccine-elicited antibody responses. Extended boosts in RV305 increased circulating antibody concentration and coverage of heterologous HIV-1 strains by V1V2-specific antibodies above estimated protective levels observed in RV144. Antibody Fc effector functions, specifically antibody-dependent cellular cytotoxicity and phagocytosis, were boosted to higher levels than was achieved in RV144. V1V2 Env IgG3, a correlate of lower HIV-1 risk, was not increased; plasma Env IgA (specifically IgA1), a correlate of increased HIV-1 risk, was elevated. The quality of the circulating polyclonal antibody response changed with each booster immunization. Remarkably, the ALVAC-HIV booster immunogen induced antibody responses post-second boost, indicating that the viral vector immunogen can be utilized to selectively enhance immune correlates of decreased HIV-1 risk. These results reveal a complex dynamic of HIV-1 immunity post-vaccination that may require careful balancing to achieve protective immunity in the vaccinated population. Trial registration: RV305 clinical trial (ClinicalTrials.gov number, NCT01435135). ClinicalTrials.gov Identifier: NCT00223080., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)
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- 2023
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20. Editorial: AIDS 40th Year.
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Zhou J, Jiang S, Zhou T, Chen Z, Jin X, Zhang W, Rerks-Ngarm S, Kramvis A, Deng K, and Zhang L
- Abstract
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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- 2023
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21. Prevalence of HPV infection among Thai schoolgirls in the north-eastern provinces in 2018: implications for HPV immunization policy.
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Vongpunsawad S, Rhee C, Nilyanimit P, Poudyal N, Jiamsiri S, Ahn HS, Lee J, Seo HW, Klinsupa W, Park S, Premsri N, Namwat C, Silaporn P, Excler JL, Kim DR, Markowitz LE, Unger ER, Rerks-Ngarm S, Lynch J, and Poovorawan Y
- Abstract
Objective: The aim of this study was to determine the prevalence of high-risk (HR) and vaccine-type human papillomavirus (HPV) infection among Thai schoolgirls who were not included in the national HPV immunization program., Methods: Cross-sectional surveys were conducted among grade 10 (15-16 years old) and grade 12 (17-18 years old) schoolgirls in two provinces of Thailand. Urine samples were collected using the Colli-Pee
Ⓡ device from November 2018 to February 2019. The samples were initially tested using CobasⓇ 4800. Subsequently, all Cobas-positive samples and 1:1 matched Cobas-negative samples were tested by AnyplexⓇ assay. Prevalences of any HPV, any HR HPV, vaccine-type HPV, and individual HR HPV types were estimated by school grade., Results: Prevalences of any HPV and any HR HPV were 11.6% and 8.6% for grade 10, and 18.5% and 12.4% for grade 12 schoolgirls, respectively. Prevalences of bivalent vaccine-type HPV infection in grades 10 and 12 were 3.4% and 4.5%, respectively. Prevalences of quadrivalent and nonavalent vaccine-type HPV infections were 4.0%/6.6% and 6.4%/10.4% in grades 10 and 12, respectively. HPV16 was the most common type detected, followed by HPV58, 51, and 52. Circulating HR HPV types were similar between the school grades., Conclusion: A substantial burden of HR HPV infections was found among unvaccinated high school girls in Thailand., Competing Interests: The authors declare that they have no competing interests., (© 2023 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.)- Published
- 2023
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22. Systematic comparison of HIV-1 Envelope-specific IgG responses induced by different vaccination regimens: Can we steer IgG recognition towards regions of viral vulnerability?
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Horvath A, Rogers L, Pollakis G, Baranov O, Pieroth N, Joseph S, Chachage M, Heitzer A, Maganga L, Msafiri F, Joachim A, Viegas E, Eller LA, Kibuuka H, Rerks-Ngarm S, Pitisuttithum P, Nitayapan S, Dhitavat J, Premsri N, Fidler S, Shattock RJ, Robb ML, Weber J, McCormack S, Munseri PJ, Lyamuya E, Nilsson C, Kroidl A, Hoelscher M, Wagner R, Geldmacher C, and Held K
- Subjects
- Humans, HIV Antibodies, Vaccination, Epitopes, Immunoglobulin G, HIV Infections prevention & control, HIV-1
- Abstract
Immunogens and vaccination regimens can influence patterns of immune-epitope recognition, steering them towards or away from epitopes of potential viral vulnerability. HIV-1 envelope (Env)-specific antibodies targeting variable region 2 (V2) or 3 (V3) correlated with protection during the RV144 trial, however, it was suggested that the immunodominant V3 region might divert antibody responses away from other relevant sites. We mapped IgG responses against linear Env epitopes in five clinical HIV vaccine trials, revealing a specific pattern of Env targeting for each regimen. Notable V2 responses were only induced in trials administering CRF01_AE based immunogens, but targeting of V3 was seen in all trials, with the soluble, trimeric CN54gp140 protein eliciting robust V3 recognition. Strong V3 targeting was linked to greater overall response, increased number of total recognised antigenic regions, and where present, stronger V2 recognition. Hence, strong induction of V3-specific antibodies did not negatively impact the targeting of other linear epitopes in this study, suggesting that the induction of antibodies against V3 and other regions of potential viral vulnerability need not be necessarily mutually exclusive., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Horvath, Rogers, Pollakis, Baranov, Pieroth, Joseph, Chachage, Heitzer, Maganga, Msafiri, Joachim, Viegas, Eller, Kibuuka, Rerks-Ngarm, Pitisuttithum, Nitayapan, Dhitavat, Premsri, Fidler, Shattock, Robb, Weber, McCormack, Munseri, Lyamuya, Nilsson, Kroidl, Hoelscher, Wagner, Geldmacher and Held.)
- Published
- 2023
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23. A community intervention effectiveness study of single dose or two doses of bivalent HPV vaccine (CERVARIX®) in female school students in Thailand.
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Jiamsiri S, Rhee C, Ahn HS, Poudyal N, Seo HW, Klinsupa W, Nilyanimit P, Premsri N, Namwat C, Vonpunsawad S, Chon Y, Park S, Kim DR, Unger ER, Markowitz L, Poovorawan Y, Rerks-Ngarm S, Excler JL, and Lynch J
- Subjects
- Cross-Sectional Studies, Female, Humans, Papillomaviridae, Students, Thailand epidemiology, Alphapapillomavirus, Papillomavirus Infections epidemiology, Papillomavirus Infections prevention & control, Papillomavirus Vaccines
- Abstract
Human papillomavirus (HPV) is a common infection principally spread through sexual activity. Most HPV infections are asymptomatic and resolve spontaneously. However, persistent infection may progress to cervical cancer. Highly efficacious HPV vaccines have been available since 2006, yet uptake into national programs has been slow in part due to cost. WHO guidelines call for a two-dose (0,6 month) schedule for girls 9-14 years of age. Post-hoc analyses of randomized trials have found high vaccine effectiveness following a single dose of vaccine. In order to provide additional data on the potential impact of single dose HPV vaccination in a real-world setting, we are conducting an effectiveness study among Thai schoolgirls. This is an observational study of a single dose (SD) or two doses (2D) of the bivalent HPV vaccine CERVARIX® (GlaxoSmithKline plc.) administered in a school-based program to 8-9,000 Grade 8 female students in two provinces of Thailand beginning in 2018; one province is assigned the SD, and the other the standard 2D regimen. The reduction in HPV vaccine-type prevalence will be assessed in each province two and four years after vaccination by comparing HPV prevalence in urine samples obtained through cross-sectional surveys of the immunized grade cohort as they age and compared to a historical "baseline" HPV prevalence of same age students., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2022
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24. A Quantitative Approach to Unravel the Role of Host Genetics in IgG-FcγR Complex Formation After Vaccination.
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Lemke MM, Theisen RM, Bozich ER, McLean MR, Lee CY, Lopez E, Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, Kratochvil S, Wines BD, Hogarth PM, Kent SJ, Chung AW, and Arnold KB
- Subjects
- Humans, Immunoglobulin G, Receptors, Fc metabolism, Vaccination, AIDS Vaccines, Receptors, IgG metabolism
- Abstract
Fc-mediated immune functions have been correlated with protection in the RV144 HIV vaccine trial and are important for immunity to a range of pathogens. IgG antibodies (Abs) that form complexes with Fc receptors (FcRs) on innate immune cells can activate Fc-mediated immune functions. Genetic variation in both IgGs and FcRs have the capacity to alter IgG-FcR complex formation via changes in binding affinity and concentration. A growing challenge lies in unraveling the importance of multiple variations, especially in the context of vaccine trials that are conducted in homogenous genetic populations. Here we use an ordinary differential equation model to quantitatively assess how IgG1 allotypes and FcγR polymorphisms influence IgG-FcγRIIIa complex formation in vaccine-relevant settings. Using data from the RV144 HIV vaccine trial, we map the landscape of IgG-FcγRIIIa complex formation predicted post-vaccination for three different IgG1 allotypes and two different FcγRIIIa polymorphisms. Overall, the model illustrates how specific vaccine interventions could be applied to maximize IgG-FcγRIIIa complex formation in different genetic backgrounds. Individuals with the G1m1,17 and G1m1,3 allotypes were predicted to be more responsive to vaccine adjuvant strategies that increase antibody FcγRIIIa affinity (e.g. glycosylation modifications), compared to the G1m-1,3 allotype which was predicted to be more responsive to vaccine boosting regimens that increase IgG1 antibody titers (concentration). Finally, simulations in mixed-allotype populations suggest that the benefit of boosting IgG1 concentration versus IgG1 affinity may be dependent upon the presence of the G1m-1,3 allotype. Overall this work provides a quantitative tool for rationally improving Fc-mediated functions after vaccination that may be important for assessing vaccine trial results in the context of under-represented genetic populations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lemke, Theisen, Bozich, McLean, Lee, Lopez, Rerks-Ngarm, Pitisuttithum, Nitayaphan, Kratochvil, Wines, Hogarth, Kent, Chung and Arnold.)
- Published
- 2022
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25. Monocyte-derived transcriptome signature indicates antibody-dependent cellular phagocytosis as a potential mechanism of vaccine-induced protection against HIV-1.
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Shangguan S, Ehrenberg PK, Geretz A, Yum L, Kundu G, May K, Fourati S, Nganou-Makamdop K, Williams LD, Sawant S, Lewitus E, Pitisuttithum P, Nitayaphan S, Chariyalertsak S, Rerks-Ngarm S, Rolland M, Douek DC, Gilbert P, Tomaras GD, Michael NL, Vasan S, and Thomas R
- Subjects
- AIDS Vaccines adverse effects, Clinical Trials as Topic, Databases, Genetic, HIV Infections genetics, HIV Infections immunology, HIV Infections virology, HIV-1 pathogenicity, Host-Pathogen Interactions, Humans, Immunogenicity, Vaccine, Monocytes immunology, Monocytes metabolism, Oligonucleotide Array Sequence Analysis, RNA-Seq, Single-Cell Analysis, Time Factors, Treatment Outcome, Vaccination, Vaccines, DNA adverse effects, AIDS Vaccines therapeutic use, Gene Expression Profiling, HIV Antibodies immunology, HIV Infections prevention & control, HIV-1 immunology, Monocytes drug effects, Phagocytosis drug effects, Transcriptome, Vaccines, DNA therapeutic use
- Abstract
A gene signature was previously found to be correlated with mosaic adenovirus 26 vaccine protection in simian immunodeficiency virus and simian-human immunodeficiency virus challenge models in non-human primates. In this report, we investigated the presence of this signature as a correlate of reduced risk in human clinical trials and potential mechanisms of protection. The absence of this gene signature in the DNA/rAd5 human vaccine trial, which did not show efficacy, strengthens our hypothesis that this signature is only enriched in studies that demonstrated protection. This gene signature was enriched in the partially effective RV144 human trial that administered the ALVAC/protein vaccine, and we find that the signature associates with both decreased risk of HIV-1 acquisition and increased vaccine efficacy (VE). Total RNA-seq in a clinical trial that used the same vaccine regimen as the RV144 HIV vaccine implicated antibody-dependent cellular phagocytosis (ADCP) as a potential mechanism of vaccine protection. CITE-seq profiling of 53 surface markers and transcriptomes of 53,777 single cells from the same trial showed that genes in this signature were primarily expressed in cells belonging to the myeloid lineage, including monocytes, which are major effector cells for ADCP. The consistent association of this transcriptome signature with VE represents a tool both to identify potential mechanisms, as with ADCP here, and to screen novel approaches to accelerate the development of new vaccine candidates., Competing Interests: SS, PE, AG, LY, GK, KM, SF, KN, LW, SS, EL, PP, SN, SC, SR, MR, DD, PG, GT, NM, SV, RT No competing interests declared
- Published
- 2021
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26. A systems approach to elucidate personalized mechanistic complexities of antibody-Fc receptor activation post-vaccination.
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Lemke MM, McLean MR, Lee CY, Lopez E, Bozich ER, Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, Kratochvil S, Wines BD, Hogarth PM, Kent SJ, Chung AW, and Arnold KB
- Subjects
- Humans, Immunoglobulin G metabolism, Models, Biological, Receptors, IgG metabolism, Reproducibility of Results, env Gene Products, Human Immunodeficiency Virus metabolism, HIV Antibodies immunology, Precision Medicine, Receptors, Fc metabolism, Systems Analysis, Vaccination
- Abstract
Immunoglobulin G (IgG) antibodies that activate Fc-mediated immune functions have been correlated with vaccine efficacy, but it is difficult to unravel the relative roles of multiple IgG and Fc receptor (FcR) features that have the capacity to influence IgG-FcR complex formation but vary on a personalized basis. Here, we develop an ordinary differential-equation model to determine how personalized variability in IgG subclass concentrations and binding affinities influence IgG-FcγRIIIa complex formation and validate it with samples from the HIV RV144 vaccine trial. The model identifies individuals who are sensitive, insensitive, or negatively affected by increases in HIV-specific IgG1, which is validated with the addition of HIV-specific IgG1 monoclonal antibodies to vaccine samples. IgG1 affinity to FcγRIIIa is also prioritized as the most influential parameter for dictating activation broadly across a population. Overall, this work presents a quantitative tool for evaluating personalized differences underlying FcR activation, which is relevant to ongoing efforts to improve vaccine efficacy., Competing Interests: The authors declare no competing interests., (© 2021 The Authors.)
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- 2021
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27. Limited Evidence for a Relationship between HIV-1 Glycan Shield Features in Early Infection and the Development of Neutralization Breadth.
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Li Y, Bai H, Sanders-Buell E, Dussupt V, Townsley S, Donofrio G, Bose M, O'Sullivan AM, Kibuuka H, Maganga L, Nitayaphan S, Kosgei J, Pitisuttithum P, Rerks-Ngarm S, Eller LA, Michael NL, Robb ML, Ake J, Vasan S, Tovanabutra S, Krebs SJ, and Rolland M
- Subjects
- Africa, Eastern epidemiology, Antibodies, Neutralizing blood, Cohort Studies, Epitopes, Glycosylation, HIV Antibodies blood, HIV Infections immunology, HIV Infections virology, Humans, Thailand epidemiology, Antibodies, Neutralizing immunology, HIV Antibodies immunology, HIV Infections epidemiology, HIV-1 immunology, Immune Evasion immunology, Polysaccharides immunology, env Gene Products, Human Immunodeficiency Virus immunology
- Abstract
Identifying whether viral features present in acute HIV-1 infection predetermine the development of neutralization breadth is critical to vaccine design. Incorporating such features in vaccine antigens could initiate cross-reactive antibody responses that could sufficiently protect vaccinees from HIV-1 infection despite the uniqueness of each founder virus. To understand the relationship between Env determinants and the development of neutralization breadth, we focused on 197 individuals enrolled in two cohorts in Thailand and East Africa (RV144 and RV217) and followed since their diagnosis in acute or early HIV-1 infection. We analyzed the distribution of variable loop lengths and glycans, as well as the predicted density of the glycan shield, and compared these envelope features to the neutralization breadth data obtained 3 years after infection ( n = 121). Our study revealed limited evidence for glycan shield features that associate with the development of neutralization breadth. While the glycan shield tended to be denser in participants who subsequently developed breadth, no significant relationship was found between the size of glycan holes and the development of neutralization breadth. The parallel analysis of 3,000 independent Env sequences showed no evidence of directional evolution of glycan shield features since the beginning of the epidemic. Together, our results highlight that glycan shield features in acute and early HIV-1 infection may not play a role determinant enough to dictate the development of neutralization breadth and instead suggest that the glycan shield's reactive properties that are associated with immune evasion may have a greater impact. IMPORTANCE A major goal of HIV-1 vaccine research is to design vaccine candidates that elicit potent broadly neutralizing antibodies (bNAbs). Different viral features have been associated with the development of bNAbs, including the glycan shield on the surface of the HIV-1 Envelope (Env). Here, we analyzed data from two cohorts of individuals who were followed from early infection to several years after infection spanning multiple HIV-1 subtypes. We compared Env glycan features in HIV-1 sequences obtained in early infection to the potency and breadth of neutralizing antibodies measured 1 to 3 years after infection. We found limited evidence of glycan shield properties that associate with the development of neutralization breadth in these cohorts. These results may have important implications for antigen design in future vaccine strategies and emphasize that HIV-1 vaccines will need to rely on a complex set of properties to elicit neutralization breadth.
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- 2021
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28. RV144 vaccine imprinting constrained HIV-1 evolution following breakthrough infection.
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Lewitus E, Sanders-Buell E, Bose M, O'Sullivan AM, Poltavee K, Li Y, Bai H, Mdluli T, Donofrio G, Slike B, Zhao H, Wong K, Chen L, Miller S, Lee J, Ahani B, Lepore S, Muhammad S, Grande R, Tran U, Dussupt V, Mendez-Rivera L, Nitayaphan S, Kaewkungwal J, Pitisuttithum P, Rerks-Ngarm S, O'Connell RJ, Janes H, Gilbert PB, Gramzinski R, Vasan S, Robb ML, Michael NL, Krebs SJ, Herbeck JT, Edlefsen PT, Mullins JI, Kim JH, Tovanabutra S, and Rolland M
- Abstract
The scale of the HIV-1 epidemic underscores the need for a vaccine. The multitude of circulating HIV-1 strains together with HIV-1's high evolvability hints that HIV-1 could adapt to a future vaccine. Here, we wanted to investigate the effect of vaccination on the evolution of the virus post-breakthrough infection. We analyzed 2,635 HIV-1 env sequences sampled up to a year post-diagnosis from 110 vaccine and placebo participants who became infected in the RV144 vaccine efficacy trial. We showed that the Env signature sites that were previously identified to distinguish vaccine and placebo participants were maintained over time. In addition, fewer sites were under diversifying selection in the vaccine group than in the placebo group. These results indicate that HIV-1 would possibly adapt to a vaccine upon its roll-out., (© The Author(s) 2021. Published by Oxford University Press.)
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- 2021
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29. Correction: RV144 HIV-1 vaccination impacts post-infection antibody responses.
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Mdluli T, Jian N, Slike B, Paquin-Proulx D, Donofrio G, Alrubayyi A, Gift S, Grande R, Bryson M, Lee A, Dussupt V, Mendez-Rivera L, Sanders-Buell E, Chenine AL, Tran U, Li Y, Brown E, Edlefsen PT, O'Connell R, Gilbert P, Nitayaphan S, Pitisuttihum P, Rerks-Ngarm S, Robb ML, Gramzinski R, Alter G, Tovanabutra S, Georgiev IS, Ackerman ME, Polonis VR, Vasan S, Michael NL, Kim JH, Eller MA, Krebs SJ, and Rolland M
- Abstract
[This corrects the article DOI: 10.1371/journal.ppat.1009101.].
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- 2021
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30. RV144 HIV-1 vaccination impacts post-infection antibody responses.
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Mdluli T, Jian N, Slike B, Paquin-Proulx D, Donofrio G, Alrubayyi A, Gift S, Grande R, Bryson M, Lee A, Dussupt V, Mendez-Riveria L, Sanders-Buell E, Chenine AL, Tran U, Li Y, Brown E, Edlefsen PT, O'Connell R, Gilbert P, Nitayaphan S, Pitisuttihum P, Rerks-Ngarm S, Robb ML, Gramzinski R, Alter G, Tovanabutra S, Georgiev IS, Ackerman ME, Polonis VR, Vasan S, Michael NL, Kim JH, Eller MA, Krebs SJ, and Rolland M
- Subjects
- Adult, Antibody Formation immunology, B-Lymphocytes immunology, Female, HIV Antibodies blood, HIV-1, Humans, Immunoglobulin G immunology, Male, Middle Aged, env Gene Products, Human Immunodeficiency Virus immunology, AIDS Vaccines immunology, HIV Antibodies immunology, HIV Infections immunology, HIV Infections prevention & control
- Abstract
The RV144 vaccine efficacy clinical trial showed a reduction in HIV-1 infections by 31%. Vaccine efficacy was associated with stronger binding antibody responses to the HIV Envelope (Env) V1V2 region, with decreased efficacy as responses wane. High levels of Ab-dependent cellular cytotoxicity (ADCC) together with low plasma levels of Env-specific IgA also correlated with decreased infection risk. We investigated whether B cell priming from RV144 vaccination impacted functional antibody responses to HIV-1 following infection. Antibody responses were assessed in 37 vaccine and 63 placebo recipients at 6, 12, and 36 months following HIV diagnosis. The magnitude, specificity, dynamics, subclass recognition and distribution of the binding antibody response following infection were different in RV144 vaccine recipients compared to placebo recipients. Vaccine recipients demonstrated increased IgG1 binding specifically to V1V2, as well as increased IgG2 and IgG4 but decreased IgG3 to HIV-1 Env. No difference in IgA binding to HIV-1 Env was detected between the vaccine and placebo recipients following infection. RV144 vaccination limited the development of broadly neutralizing antibodies post-infection, but enhanced Fc-mediated effector functions indicating B cell priming by RV144 vaccination impacted downstream antibody function. However, these functional responses were not associated with clinical markers of disease progression. These data reveal that RV144 vaccination primed B cells towards specific binding and functional antibody responses following HIV-1 infection., Competing Interests: The authors have declared that no competing interests exist.
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- 2020
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31. IgG3 collaborates with IgG1 and IgA to recruit effector function in RV144 vaccinees.
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Fischinger S, Dolatshahi S, Jennewein MF, Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, Michael N, Vasan S, Ackerman ME, Streeck H, and Alter G
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- AIDS Vaccines immunology, Case-Control Studies, HIV Infections immunology, HIV Infections virology, Humans, Phagocytosis, AIDS Vaccines administration & dosage, Antibody Formation, HIV Antibodies immunology, HIV Infections prevention & control, HIV-1 immunology, Immunoglobulin A immunology, Immunoglobulin G immunology
- Abstract
While the RV144 HIV vaccine trial led to moderately reduced risk of HIV acquisition, emerging data from the HVTN702 trial point to the critical need to reexamine RV144-based correlates of reduced risk of protection. While in RV144, the induction of V2-binding, non-IgA, IgG3 antibody responses with nonneutralizing functions were linked to reduced risk of infection, the interactions between these signatures remain unclear. Thus, here we comprehensively profile the humoral immune response in 300 RV144 vaccinees to decipher the relationships between humoral biomarkers of protection. We found that vaccine-specific IgG1, IgG3, and IgA were highly correlated. However, ratios of IgG1:IgG3:IgA provided insights into subclass/isotype polyclonal functional regulation. For instance, in the absence of high IgG1 levels, IgG3 antibodies exhibited limited functional activity, pointing to IgG3 as a critical contributor, but not sole driver, of effective antiviral humoral immunity. Higher IgA levels were linked to enhanced antibody effector function, including neutrophil phagocytosis (ADNP), complement deposition (ADCD), and antibody-dependent NK degranulation (CD107a), some of which were increased in infected vaccinees in a case/control data set, suggesting that IgA-driven functions compromised immunity. These data highlight the interplay between IgG1, IgG3, and IgA, pointing to the need to profile the relationships between subclass/isotype selection.
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- 2020
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32. Protein-based, but not viral vector alone, HIV vaccine boosting drives an IgG1-biased polyfunctional humoral immune response.
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Fischinger S, Shin S, Boudreau CM, Ackerman M, Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, Kim JH, Robb ML, Michael NL, O'Connell RJ, Vasan S, Streeck H, and Alter G
- Subjects
- Antibody-Dependent Cell Cytotoxicity immunology, HIV Antigens immunology, HIV Infections immunology, Humans, Immunity, Humoral immunology, Immunization, Secondary methods, AIDS Vaccines immunology, HIV Antibodies immunology, HIV Infections prevention & control, HIV-1 immunology
- Abstract
The RV144 HIV-1 vaccine trial results showed moderate reduction in viral infections among vaccinees as well as induction of antibody-dependent cellular cytotoxicity and vaccine-specific IgG and IgG3 responses directed at variable loop regions 1 and 2 of the HIV envelope protein. However, with the recent failure of the HVTN 702 clinical trial, comprehensive profiling of humoral immune responses may provide insight for these disappointing results. One of the changes included in the HVTN 702 study was the addition of a late boost, aimed at augmenting peak immunity and durability. The companion vaccine trial RV305 was designed to permit the evaluation of the immunologic impact of late boosting with either the boosting protein antigen alone, the canarypox viral vector ALVAC alone, or a combination of both. Although previous data showed elevated levels of IgG antibodies in both boosting arms, regardless of ALVAC-HIV vector incorporation, the effect on shaping antibody effector function remains unclear. Thus, here we analyzed the antibody and functional profile induced by RV305 boosting regimens and found that although IgG1 levels increased in both arms that included protein boosting, IgG3 levels were reduced compared with the original RV144 vaccine strategy. Most functional responses increased upon protein boosting, regardless of the viral vector-priming agent incorporation. These data suggest that the addition of a late protein boost alone is sufficient to increase functionally potent vaccine-specific antibodies previously associated with reduced risk of infection with HIV.
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- 2020
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33. Boosting with AIDSVAX B/E Enhances Env Constant Region 1 and 2 Antibody-Dependent Cellular Cytotoxicity Breadth and Potency.
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Easterhoff D, Pollara J, Luo K, Tolbert WD, Young B, Mielke D, Jha S, O'Connell RJ, Vasan S, Kim J, Michael NL, Excler JL, Robb ML, Rerks-Ngarm S, Kaewkungwal J, Pitisuttithum P, Nitayaphan S, Sinangil F, Tartaglia J, Phogat S, Kepler TB, Alam SM, Wiehe K, Saunders KO, Montefiori DC, Tomaras GD, Moody MA, Pazgier M, Haynes BF, and Ferrari G
- Subjects
- Antibodies, Monoclonal immunology, Antibody Formation immunology, Antibody Specificity immunology, Antibody-Dependent Cell Cytotoxicity immunology, Epitopes immunology, HIV Antibodies immunology, HIV Antibodies ultrastructure, HIV Envelope Protein gp120 ultrastructure, HIV Infections immunology, HIV-1 immunology, Humans, Immunization, Secondary methods, Immunoglobulin G immunology, AIDS Vaccines immunology, HIV Envelope Protein gp120 immunology
- Abstract
Induction of protective antibodies is a critical goal of HIV-1 vaccine development. One strategy is to induce nonneutralizing antibodies (NNAbs) that kill virus-infected cells, as these antibody specificities have been implicated in slowing HIV-1 disease progression and in protection. HIV-1 Env constant region 1 and 2 (C1C2) monoclonal antibodies (MAbs) frequently mediate potent antibody-dependent cellular cytotoxicity (ADCC), making them an important vaccine target. Here, we explore the effect of delayed and repetitive boosting of RV144 vaccine recipients with AIDSVAX B/E on the C1C2-specific MAb repertoire. It was found that boosting increased clonal lineage-specific ADCC breadth and potency. A ligand crystal structure of a vaccine-induced broad and potent ADCC-mediating C1C2-specific MAb showed that it bound a highly conserved Env gp120 epitope. Thus, boosting to affinity mature these types of IgG C1C2-specific antibody responses may be one method by which to make an improved HIV vaccine with higher efficacy than that seen in the RV144 trial. IMPORTANCE Over one million people become infected with HIV-1 each year, making the development of an efficacious HIV-1 vaccine an important unmet medical need. The RV144 human HIV-1 vaccine regimen is the only HIV-1 clinical trial to date to demonstrate vaccine efficacy. An area of focus has been on identifying ways by which to improve upon RV144 vaccine efficacy. The RV305 HIV-1 vaccine regimen was a follow-up boost of RV144 vaccine recipients that occurred 6 to 8 years after the conclusion of RV144. Our study focused on the effect of delayed boosting in humans on the vaccine-induced Env constant region 1 and 2 (C1C2)-specific antibody repertoire. It was found that boosting with an HIV-1 Env vaccine increased C1C2-specific antibody-dependent cellular cytotoxicity potency and breadth., (Copyright © 2020 Easterhoff et al.)
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- 2020
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34. Landscapes of binding antibody and T-cell responses to pox-protein HIV vaccines in Thais and South Africans.
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Zhao LP, Fiore-Gartland A, Carpp LN, Cohen KW, Rouphael N, Fleurs L, Dintwe O, Zhao M, Moodie Z, Fong Y, Garrett N, Huang Y, Innes C, Janes HE, Lazarus E, Michael NL, Nitayaphan S, Pitisuttithum P, Rerks-Ngarm S, Robb ML, De Rosa SC, Corey L, Gray GE, Seaton KE, Yates NL, McElrath MJ, Frahm N, Tomaras GD, and Gilbert PB
- Subjects
- AIDS Vaccines immunology, Adolescent, Adult, Antibody Formation immunology, Female, HIV Antibodies metabolism, HIV Infections epidemiology, HIV Infections immunology, Humans, Male, South Africa epidemiology, Thailand epidemiology, Young Adult, AIDS Vaccines administration & dosage, Antibodies, Neutralizing immunology, CD4-Positive T-Lymphocytes immunology, HIV Antibodies immunology, HIV Antigens immunology, HIV Infections prevention & control, HIV-1 immunology
- Abstract
Background: HIV vaccine trials routinely measure multiple vaccine-elicited immune responses to compare regimens and study their potential associations with protection. Here we employ unsupervised learning tools facilitated by a bidirectional power transformation to explore the multivariate binding antibody and T-cell response patterns of immune responses elicited by two pox-protein HIV vaccine regimens. Both regimens utilized a recombinant canarypox vector (ALVAC-HIV) prime and a bivalent recombinant HIV-1 Envelope glycoprotein 120 subunit boost. We hypothesized that within each trial, there were participant subgroups sharing similar immune responses and that their frequencies differed across trials., Methods and Findings: We analyzed data from three trials-RV144 (NCT00223080), HVTN 097 (NCT02109354), and HVTN 100 (NCT02404311), the latter of which was pivotal in advancing the tested pox-protein HIV vaccine regimen to the HVTN 702 Phase 2b/3 efficacy trial. We found that bivariate CD4+ T-cell and anti-V1V2 IgG/IgG3 antibody response patterns were similar by age, sex-at-birth, and body mass index, but differed for the pox-protein clade AE/B alum-adjuvanted regimen studied in RV144 and HVTN 097 (PAE/B/alum) compared to the pox-protein clade C/C MF59-adjuvanted regimen studied in HVTN 100 (PC/MF59). Specifically, more PAE/B/alum recipients had low CD4+ T-cell and high anti-V1V2 IgG/IgG3 responses, and more PC/MF59 recipients had broad responses of both types. Analyses limited to "vaccine-matched" antigens suggested that some of the differences in responses between the regimens could have been due to antigens in the assays that did not match the vaccine immunogens. Our approach was also useful in identifying subgroups with unusually absent or high co-responses across assay types, flagging individuals for further characterization by functional assays. We also found that co-responses of anti-V1V2 IgG/IgG3 and CD4+ T cells had broad variability. As additional immune response assays are standardized and validated, we anticipate our framework will be increasingly valuable for multivariate analysis., Conclusions: Our approach can be used to advance vaccine development objectives, including the characterization and comparison of candidate vaccine multivariate immune responses and improved design of studies to identify correlates of protection. For instance, results suggested that HVTN 702 will have adequate power to interrogate immune correlates involving anti-V1V2 IgG/IgG3 and CD4+ T-cell co-readouts, but will have lower power to study anti-gp120/gp140 IgG/IgG3 due to their lower dynamic ranges. The findings also generate hypotheses for future testing in experimental and computational analyses aimed at achieving a mechanistic understanding of vaccine-elicited immune response heterogeneity., Competing Interests: The authors of this manuscript have read the journal's policy and have the following competing interests: LC, ZM, YF, NG, GEG, HEJ, MJM, NR, SCR, NF, GDT, and PBG are recipients of funding from the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH), and this publication is a result of activities funded by the NIAID. PBG and GDT are recipients of funding from the Bill and Melinda Gates Foundation, and this publication is a result of activities funded by the BMGF. SR-N is an employee of the Department of Disease Control in the Ministry of Public Heath (Thailand), and this publication is a result of activities conducted through facilities of the Thailand MPH. NLM was an employee of the U.S. Army and MLR is an employee of the Henry Jackson Foundation components of the Military HIV Research Program (MHRP)/Walter Reed Army Institute of Research, which is supported by the US Department of Defense, and this publication is a result of activities partially funded by the DOD. HEJ is a recipient of funding from the National Cancer Institute of the NIH. YH is a recipient of funding from the National Institute of General Medical Sciences of the NIH. AFG is the recipient of funding from the Infectious Disease Research Institute. LC has received grants from Gilead, Sanofi Pasteur Biologics and Immune Design Corp. PBG is the recipient of a contract from Sanofi Pasteur and has served as an unpaid consultant at advisory meetings to Sanofi Pasteur. LNC, ZM, YH, YF, and PBG have received salary support from the contract with Sanofi Pasteur and ZM, YH, YF, and PBG have received support for travel to meetings from Sanofi Pasteur. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
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- 2020
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35. HIV vaccine delayed boosting increases Env variable region 2-specific antibody effector functions.
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Easterhoff D, Pollara J, Luo K, Janus B, Gohain N, Williams LD, Tay MZ, Monroe A, Peachman K, Choe M, Min S, Lusso P, Zhang P, Go EP, Desaire H, Bonsignori M, Hwang KK, Beck C, Kakalis M, O'Connell RJ, Vasan S, Kim JH, Michael NL, Excler JL, Robb ML, Rerks-Ngarm S, Kaewkungwal J, Pitisuttithum P, Nitayaphan S, Sinangil F, Tartaglia J, Phogat S, Wiehe K, Saunders KO, Montefiori DC, Tomaras GD, Moody MA, Arthos J, Rao M, Joyce MG, Ofek G, Ferrari G, and Haynes BF
- Subjects
- AIDS Vaccines chemistry, Antibodies, Monoclonal chemistry, Antibodies, Monoclonal genetics, Antibodies, Monoclonal immunology, Antibody-Dependent Cell Cytotoxicity, Clinical Trials as Topic, Epitopes genetics, Epitopes immunology, HIV Antibodies chemistry, HIV Antibodies genetics, HIV Infections immunology, HIV Infections prevention & control, HIV-1 immunology, Humans, Immunization, Secondary, Models, Molecular, Mutation, Protein Conformation, Viral Vaccines, X-Ray Diffraction, env Gene Products, Human Immunodeficiency Virus genetics, env Gene Products, Human Immunodeficiency Virus immunology, AIDS Vaccines immunology, HIV Antibodies immunology, Immunoglobulin Variable Region genetics, Immunoglobulin Variable Region immunology
- Abstract
In the RV144 HIV-1 phase III trial, vaccine efficacy directly correlated with the magnitude of the variable region 2-specific (V2-specific) IgG antibody response, and in the presence of low plasma IgA levels, with the magnitude of plasma antibody-dependent cellular cytotoxicity. Reenrollment of RV144 vaccinees in the RV305 trial offered the opportunity to define the function, maturation, and persistence of vaccine-induced V2-specific and other mAb responses after boosting. We show that the RV144 vaccine regimen induced persistent V2 and other HIV-1 envelope-specific memory B cell clonal lineages that could be identified throughout the approximately 11-year vaccination period. Subsequent boosts increased somatic hypermutation, a critical requirement for antibody affinity maturation. Characterization of 22 vaccine-induced V2-specific mAbs with epitope specificities distinct from previously characterized RV144 V2-specific mAbs CH58 and CH59 found increased in vitro antibody-mediated effector functions. Thus, when inducing non-neutralizing antibodies, one method by which to improve HIV-1 vaccine efficacy may be through late boosting to diversify the V2-specific response to increase the breadth of antibody-mediated anti-HIV-1 effector functions.
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- 2020
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36. Modulation of Vaccine-Induced CD4 T Cell Functional Profiles by Changes in Components of HIV Vaccine Regimens in Humans.
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Pissani F, Schulte B, Eller MA, Schultz BT, Ratto-Kim S, Marovich M, Thongcharoen P, Sriplienchan S, Rerks-Ngarm S, Pitisuttithum P, Esser S, Alter G, Robb ML, Kim JH, Michael NL, and Streeck H
- Subjects
- AIDS Vaccines genetics, Antibodies, Neutralizing immunology, CD8-Positive T-Lymphocytes drug effects, CD8-Positive T-Lymphocytes virology, Cells, Cultured, HIV Infections immunology, HIV Infections virology, HIV-1 drug effects, HIV-1 genetics, Humans, Vaccination, AIDS Vaccines classification, AIDS Vaccines immunology, CD8-Positive T-Lymphocytes immunology, HIV Antibodies immunology, HIV Envelope Protein gp120 immunology, HIV Infections prevention & control, HIV-1 immunology
- Abstract
To date, six vaccine strategies have been evaluated in clinical trials for their efficacy at inducing protective immune responses against HIV infection. However, only the ALVAC-HIV/AIDSVAX B/E vaccine (RV144 trial) has demonstrated protection, albeit modestly (31%; P = 0.03). One potential correlate of protection was a low-frequency HIV-specific CD4 T cell population with diverse functionality. Although CD4 T cells, particularly T follicular helper (Tfh) cells, are critical for effective antibody responses, most studies involving HIV vaccines have focused on humoral immunity or CD8 T cell effector responses, and little is known about the functionality and frequency of vaccine-induced CD4 T cells. We therefore assessed responses from several phase I/II clinical trials and compared them to responses to natural HIV-1 infection. We found that all vaccines induced a lower magnitude of HIV-specific CD4 T cell responses than that observed for chronic infection. Responses differed in functionality, with a CD40 ligand (CD40L)-dominated response and more Tfh cells after vaccination, whereas chronic HIV infection provoked tumor necrosis factor alpha (TNF-α)-dominated responses. The vaccine delivery route further impacted CD4 T cells, showing a stronger Th1 polarization after dendritic cell delivery than after intramuscular vaccination. In prime/boost regimens, the choice of prime and boost influenced the functional profile of CD4 T cells to induce more or less polyfunctionality. In summary, vaccine-induced CD4 T cell responses differ remarkably between vaccination strategies, modes of delivery, and boosts and do not resemble those induced by chronic HIV infection. Understanding the functional profiles of CD4 T cells that best facilitate protective antibody responses will be critical if CD4 T cell responses are to be considered a clinical trial go/no-go criterion. IMPORTANCE Only one HIV-1 candidate vaccine strategy has shown protection, albeit marginally (31%), against HIV-1 acquisition, and correlates of protection suggested that a multifunctional CD4 T cell immune response may be important for this protective effect. Therefore, the functional phenotypes of HIV-specific CD4 T cell responses induced by different phase I and phase II clinical trials were assessed to better show how different vaccine strategies influence the phenotype and function of HIV-specific CD4 T cell immune responses. The significance of this research lies in our comprehensive comparison of the compositions of the T cell immune responses to different HIV vaccine modalities. Specifically, our work allows for the evaluation of vaccination strategies in terms of their success at inducing Tfh cell populations., (Copyright © 2018 American Society for Microbiology.)
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- 2018
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37. Novel Strategy To Adapt Simian-Human Immunodeficiency Virus E1 Carrying env from an RV144 Volunteer to Rhesus Macaques: Coreceptor Switch and Final Recovery of a Pathogenic Virus with Exclusive R5 Tropism.
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Scinto HB, Gupta S, Thorat S, Mukhtar MM, Griffiths A, Delgado J, Plake E, Vyas HK, Strickland A, Byrareddy SN, Montefiori DC, LaBranche C, Pal R, Treece J, Orndorff S, Ferrari MG, Weiss D, Chenine AL, McLinden R, Michael N, Kim JH, Robb ML, Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, and Ruprecht RM
- Subjects
- Animals, Humans, Macaca mulatta, Proviruses genetics, Receptors, CCR5 metabolism, Thailand, Viral Load, Viremia, Virus Replication, Volunteers, Gene Products, env, HIV Infections virology, HIV-1 pathogenicity, Leukocytes, Mononuclear virology, Simian Acquired Immunodeficiency Syndrome virology, Simian Immunodeficiency Virus pathogenicity, Tropism
- Abstract
The phase III RV144 human immunodeficiency virus (HIV) vaccine trial conducted in Thailand remains the only study to show efficacy in decreasing the HIV acquisition risk. In Thailand, circulating recombinant forms of HIV clade A/E (CRF01_AE) predominate; in such viruses, env originates from clade E (HIV-E). We constructed a simian-human immunodeficiency virus (SHIV) chimera carrying env isolated from an RV144 placebo recipient in the SHIV-1157ipd3N4 backbone. The latter contains long terminal repeats (LTRs) with duplicated NF-κB sites, thus resembling HIV LTRs. We devised a novel strategy to adapt the parental infectious molecular clone (IMC), R5 SHIV-E1, to rhesus macaques: the simultaneous depletion of B and CD8
+ cells followed by the intramuscular inoculation of proviral DNA and repeated administrations of cell-free virus. High-level viremia and CD4+ T-cell depletion ensued. Passage 3 virus unexpectedly caused acute, irreversible CD4+ T-cell loss; the partially adapted SHIV had become dual tropic. Virus and IMCs with exclusive R5 tropism were reisolated from earlier passages, combined, and used to complete adaptation through additional macaques. The final isolate, SHIV-E1p5, remained solely R5 tropic. It had a tier 2 neutralization phenotype, was mucosally transmissible, and was pathogenic. Deep sequencing revealed 99% Env amino acid sequence conservation; X4-only and dual-tropic strains had evolved independently from an early branch of parental SHIV-E1. To conclude, our primate model data reveal that SHIV-E1p5 recapitulates important aspects of HIV transmission and pathobiology in humans. IMPORTANCE Understanding the protective principles that lead to a safe, effective vaccine against HIV in nonhuman primate (NHP) models requires test viruses that allow the evaluation of anti-HIV envelope responses. Reduced HIV acquisition risk in RV144 has been linked to nonneutralizing IgG antibodies with a range of effector activities. Definitive experiments to decipher the mechanisms of the partial protection observed in RV144 require passive-immunization studies in NHPs with a relevant test virus. We have generated such a virus by inserting env from an RV144 placebo recipient into a SHIV backbone with HIV-like LTRs. The final SHIV-E1p5 isolate, grown in rhesus monkey peripheral blood mononuclear cells, was mucosally transmissible and pathogenic. Earlier SHIV-E passages showed a coreceptor switch, again mimicking HIV biology in humans. Thus, our series of SHIV-E strains mirrors HIV transmission and disease progression in humans. SHIV-E1p5 represents a biologically relevant tool to assess prevention strategies., (Copyright © 2018 American Society for Microbiology.)- Published
- 2018
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38. Characterization of HIV-1 gp120 antibody specificities induced in anogenital secretions of RV144 vaccine recipients after late boost immunizations.
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Akapirat S, Karnasuta C, Vasan S, Rerks-Ngarm S, Pitisuttithum P, Madnote S, Savadsuk H, Rittiroongrad S, Puangkaew J, Phogat S, Tartaglia J, Sinangil F, de Souza MS, Excler JL, Kim JH, Robb ML, Michael NL, Ngauy V, O'Connell RJ, and Karasavvas N
- Subjects
- Adolescent, Adult, Anal Canal immunology, Antibody Formation, Antibody Specificity, Double-Blind Method, Enzyme-Linked Immunosorbent Assay, Female, Follow-Up Studies, HIV Antibodies immunology, HIV Infections immunology, HIV-1, Humans, Immunization, Immunoglobulin A immunology, Immunoglobulin G immunology, Male, Recombinant Proteins immunology, Young Adult, AIDS Vaccines therapeutic use, HIV Envelope Protein gp120 immunology, HIV Infections prevention & control, Immunity, Mucosal, Immunization, Secondary
- Abstract
Sexual transmission is the principal driver of the human immunodeficiency virus (HIV) pandemic. Understanding HIV vaccine-induced immune responses at mucosal surfaces can generate hypotheses regarding mechanisms of protection, and may influence vaccine development. The RV144 (ClinicalTrials.gov NCT00223080) efficacy trial showed protection against HIV infections but mucosal samples were not collected, therefore, the contribution of mucosal antibodies to preventing HIV-1 acquisition is unknown. Here, we report the generation, magnitude and persistence of antibody responses to recombinant gp120 envelope and antigens including variable one and two loop scaffold antigens (gp70V1V2) previously shown to correlate with risk in RV144. We evaluated antibody responses to gp120 A244gD and gp70V1V2 92TH023 (both CRF01_AE) and Case A2 (subtype B) in cervico-vaginal mucus (CVM), seminal plasma (SP) and rectal secretions (RS) from HIV-uninfected RV144 vaccine recipients, who were randomized to receive two late boosts of ALVAC-HIV/AIDSVAX®B/E, AIDSVAX®B/E, or ALVAC-HIV alone at 0 and 6 months. Late vaccine boosting increased IgG geometric mean titers (GMT) to gp120 A244gD in AIDSVAX®B/E and ALVAC-HIV/AIDSVAX®B/E CVM (28 and 17 fold, respectively), followed by SP and RS. IgG to gp70V1V2 92TH023 increased in AIDSVAX®B/E and ALVAC-HIV/AIDSVAX®B/E CVM (11-17 fold) and SP (2 fold) two weeks post first boost. IgG to Case A2 was only detected in AIDSVAX®B/E and ALVAC-HIV/AIDSVAX®B/E CVM. Mucosal IgG to gp120 A244gD (CVM, SP, RS), gp70V1V2 92TH023 (CVM, SP), and Case A2 (CVM) correlated with plasma IgG levels (p<0.001). Although the magnitude of IgG responses declined after boosting, anti-gp120 A244gD IgG responses in CVM persisted for 12 months post final vaccination. Further studies in localization, persistence and magnitude of envelope specific antibodies (IgG and dimeric IgA) in anogenital secretions will help determine their role in preventing mucosal HIV acquisition.
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- 2018
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39. HIV-1 Envelope Glycoproteins from Diverse Clades Differentiate Antibody Responses and Durability among Vaccinees.
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Yates NL, deCamp AC, Korber BT, Liao HX, Irene C, Pinter A, Peacock J, Harris LJ, Sawant S, Hraber P, Shen X, Rerks-Ngarm S, Pitisuttithum P, Nitayapan S, Berman PW, Robb ML, Pantaleo G, Zolla-Pazner S, Haynes BF, Alam SM, Montefiori DC, and Tomaras GD
- Subjects
- AIDS Vaccines genetics, Animals, HIV Envelope Protein gp120 genetics, HIV Infections genetics, HIV-1 genetics, Humans, Macaca mulatta, AIDS Vaccines immunology, Genetic Variation immunology, HIV Antibodies immunology, HIV Envelope Protein gp120 immunology, HIV Infections immunology, HIV-1 immunology
- Abstract
Induction of broadly cross-reactive antiviral humoral responses with the capacity to target globally diverse circulating strains is a key goal for HIV-1 immunogen design. A major gap in the field is the identification of diverse HIV-1 envelope antigens to evaluate vaccine regimens for binding antibody breadth. In this study, we define unique antigen panels to map HIV-1 vaccine-elicited antibody breadth and durability. Diverse HIV-1 envelope glycoproteins were selected based on genetic and geographic diversity to cover the global epidemic, with a focus on sexually acquired transmitted/founder viruses with a tier 2 neutralization phenotype. Unique antigenicity was determined by nonredundancy (Spearman correlation), and antigens were clustered using partitioning around medoids (PAM) to identify antigen diversity. Cross-validation demonstrated that the PAM method was better than selection by reactivity and random selection. Analysis of vaccine-elicited V1V2 binding antibody in longitudinal samples from the RV144 clinical trial revealed the striking heterogeneity among individual vaccinees in maintaining durable responses. These data support the idea that a major goal for vaccine development is to improve antibody levels, breadth, and durability at the population level. Elucidating the level and durability of vaccine-elicited binding antibody breadth needed for protection is critical for the development of a globally efficacious HIV vaccine. IMPORTANCE The path toward an efficacious HIV-1 vaccine will require characterization of vaccine-induced immunity that can recognize and target the highly genetically diverse virus envelope glycoproteins. Antibodies that target the envelope glycoproteins, including diverse sequences within the first and second hypervariable regions (V1V2) of gp120, were identified as correlates of risk for the one partially efficacious HIV-1 vaccine. To build upon this discovery, we experimentally and computationally evaluated humoral responses to define envelope glycoproteins representative of the antigenic diversity of HIV globally. These diverse envelope antigens distinguished binding antibody breadth and durability among vaccine candidates, thus providing insights for advancing the most promising HIV-1 vaccine candidates., (Copyright © 2018 Yates et al.)
- Published
- 2018
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40. HIV-1-Specific IgA Monoclonal Antibodies from an HIV-1 Vaccinee Mediate Galactosylceramide Blocking and Phagocytosis.
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Wills S, Hwang KK, Liu P, Dennison SM, Tay MZ, Shen X, Pollara J, Lucas JT, Parks R, Rerks-Ngarm S, Pitisuttithum P, Nitayapan S, Kaewkungwal J, Thomas R, Kim JH, Michael NL, Robb ML, McRaven M, Montefiori DC, Hope TJ, Liao HX, Moody MA, Ferrari G, Haynes BF, Alam SM, Bonsignori M, and Tomaras GD
- Subjects
- Antibodies, Blocking pharmacology, Antibodies, Monoclonal pharmacology, Cell Line, HIV Antibodies pharmacology, Humans, Immunoglobulin A pharmacology, Phagocytosis drug effects, AIDS Vaccines immunology, Antibodies, Blocking immunology, Antibodies, Monoclonal immunology, Galactosylceramides immunology, HIV Antibodies immunology, HIV-1 immunology, Immunoglobulin A immunology, Phagocytosis immunology
- Abstract
Vaccine-elicited humoral immune responses comprise an array of antibody forms and specificities, with only a fraction contributing to protective host immunity. Elucidation of antibody effector functions responsible for protective immunity against human immunodeficiency virus type 1 (HIV-1) acquisition is a major goal for the HIV-1 vaccine field. Immunoglobulin A (IgA) is an important part of the host defense against pathogens; however, little is known about the role of vaccine-elicited IgA and its capacity to mediate antiviral functions. To identify the antiviral functions of HIV-1-specific IgA elicited by vaccination, we cloned HIV-1 envelope-specific IgA monoclonal antibodies (MAbs) by memory B cell cultures from peripheral blood mononuclear cells from an RV144 vaccinee and produced two IgA clonal cell lines (HG129 and HG130) producing native, nonrecombinant IgA MAbs. The HG129 and HG130 MAbs mediated phagocytosis by monocytes, and HG129 blocked HIV-1 Env glycoprotein binding to galactosylceramide, an alternative HIV-1 receptor. These findings elucidate potential antiviral functions of vaccine-elicited HIV-1 envelope-specific IgA that may act to block HIV-1 acquisition at the portal of entry by preventing HIV-1 binding to galactosylceramide and mediating antibody Fc receptor-mediated virion phagocytosis. Furthermore, these findings highlight the complex and diverse interactions of vaccine-elicited IgA with pathogens that depend on IgA fine specificity and form (e.g., multimeric or monomeric) in the systemic circulation and mucosal compartments. IMPORTANCE Host-pathogen interactions in vivo involve numerous immune mechanisms that can lead to pathogen clearance. Understanding the nature of antiviral immune mechanisms can inform the design of efficacious HIV-1 vaccine strategies. Evidence suggests that both neutralizing and nonneutralizing antibodies can mediate some protection against HIV in animal models. Although numerous studies have characterized the functional properties of HIV-1-specific IgG, more studies are needed on the functional attributes of HIV-1-specific IgA, specifically for vaccine-elicited IgA. Characterization of the functional properties of HIV-1 Env-specific IgA monoclonal antibodies from human vaccine clinical trials are critical toward understanding the capacity of the host immune response to block HIV-1 acquisition., (Copyright © 2018 Wills et al.)
- Published
- 2018
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41. Distinct susceptibility of HIV vaccine vector-induced CD4 T cells to HIV infection.
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Auclair S, Liu F, Niu Q, Hou W, Churchyard G, Morgan C, Frahm N, Nitayaphan S, Pitisuthithum P, Rerks-Ngarm S, Kimata JT, Soong L, Franchini G, Robb M, Kim J, Michael N, and Hu H
- Subjects
- AIDS Vaccines administration & dosage, Adenoviridae genetics, Adenoviridae immunology, CD4-Positive T-Lymphocytes virology, Cells, Cultured, Disease Susceptibility immunology, Humans, Leukocytes, Mononuclear immunology, Lymphocyte Activation genetics, AIDS Vaccines immunology, CD4-Positive T-Lymphocytes immunology, Genetic Vectors immunology, HIV Infections immunology, HIV-1 immunology
- Abstract
The concerns raised from adenovirus 5 (Ad5)-based HIV vaccine clinical trials, where excess HIV infections were observed in some vaccine recipients, have highlighted the importance of understanding host responses to vaccine vectors and the HIV susceptibility of vector-specific CD4 T cells in HIV vaccination. Our recent study reported that human Ad5-specific CD4 T cells induced by Ad5 vaccination (RV156A trial) are susceptible to HIV. Here we further investigated the HIV susceptibility of vector-specific CD4 T cells induced by ALVAC, a canarypox viral vector tested in the Thai trial RV144, as compared to Ad5 vector-specific CD4 T cells in the HVTN204 trial. We showed that while Ad5 vector-specific CD4 T cells were readily susceptible to HIV, ALVAC-specific CD4 T cells in RV144 PBMC were substantially less susceptible to both R5 and X4 HIV in vitro. The lower HIV susceptibility of ALVAC-specific CD4 T cells was associated with the reduced surface expression of HIV entry co-receptors CCR5 and CXCR4 on these cells. Phenotypic analyses identified that ALVAC-specific CD4 T cells displayed a strong Th1 phenotype, producing higher levels of IFN-γ and CCL4 (MIP-1β) but little IL-17. Of interest, ALVAC and Ad5 vectors induced distinct profiles of vector-specific CD8 vs. CD4 T-cell proliferative responses in PBMC, with ALVAC preferentially inducing CD8 T-cell proliferation, while Ad5 vector induced CD4 T-cell proliferation. Depletion of ALVAC-, but not Ad5-, induced CD8 T cells in PBMC led to a modest increase in HIV infection of vector-specific CD4 T cells, suggesting a role of ALVAC-specific CD8 T cells in protecting ALVAC-specific CD4 T cells from HIV. Taken together, our data provide strong evidence for distinct HIV susceptibility of CD4 T cells induced by different vaccine vectors and highlight the importance of better evaluating anti-vector responses in HIV vaccination.
- Published
- 2018
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42. Monoclonal Antibodies, Derived from Humans Vaccinated with the RV144 HIV Vaccine Containing the HVEM Binding Domain of Herpes Simplex Virus (HSV) Glycoprotein D, Neutralize HSV Infection, Mediate Antibody-Dependent Cellular Cytotoxicity, and Protect Mice from Ocular Challenge with HSV-1.
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Wang K, Tomaras GD, Jegaskanda S, Moody MA, Liao HX, Goodman KN, Berman PW, Rerks-Ngarm S, Pitisuttithum P, Nitayapan S, Kaewkungwal J, Haynes BF, and Cohen JI
- Subjects
- Animals, Antibodies, Monoclonal administration & dosage, Antibody-Dependent Cell Cytotoxicity immunology, Cell Line, Eye Diseases virology, Female, HIV Envelope Protein gp120 genetics, Herpes Simplex immunology, Herpes Simplex virology, Humans, Killer Cells, Natural immunology, Leukocytes, Mononuclear immunology, Lymphocyte Activation immunology, Mice, Mice, Inbred BALB C, Simplexvirus genetics, Viral Envelope Proteins genetics, AIDS Vaccines immunology, Antibodies, Monoclonal immunology, Eye Diseases prevention & control, HIV Envelope Protein gp120 immunology, Herpes Simplex prevention & control, Receptors, Tumor Necrosis Factor, Member 14 immunology, Simplexvirus immunology, Viral Envelope Proteins immunology
- Abstract
The RV144 HIV vaccine trial included a recombinant HIV glycoprotein 120 (gp120) construct fused to a small portion of herpes simplex virus 1 (HSV-1) glycoprotein D (gD) so that the first 40 amino acids of gp120 were replaced by the signal sequence and the first 27 amino acids of the mature form of gD. This region of gD contains most of the binding site for HVEM, an HSV receptor important for virus infection of epithelial cells and lymphocytes. RV144 induced antibodies to HIV that were partially protective against infection, as well as antibodies to HSV. We derived monoclonal antibodies (MAbs) from peripheral blood B cells of recipients of the RV144 HIV vaccine and showed that these antibodies neutralized HSV-1 infection in cells expressing HVEM, but not the other major virus receptor, nectin-1. The MAbs mediated antibody-dependent cellular cytotoxicity (ADCC), and mice that received the MAbs and were then challenged by corneal inoculation with HSV-1 had reduced eye disease, shedding, and latent infection. To our knowledge, this is the first description of MAbs derived from human recipients of a vaccine that specifically target the HVEM binding site of gD. In summary, we found that monoclonal antibodies derived from humans vaccinated with the HVEM binding domain of HSV-1 gD (i) neutralized HSV-1 infection in a cell receptor-specific manner, (ii) mediated ADCC, and (iii) reduced ocular disease in virus-infected mice. IMPORTANCE Herpes simplex virus 1 (HSV-1) causes cold sores and neonatal herpes and is a leading cause of blindness. Despite many trials, no HSV vaccine has been approved. Nectin-1 and HVEM are the two major cellular receptors for HSV. These receptors are expressed at different levels in various tissues, and the role of each receptor in HSV pathogenesis is not well understood. We derived human monoclonal antibodies from persons who received the HIV RV144 vaccine that contained the HVEM binding domain of HSV-1 gD fused to HIV gp120. These antibodies were able to specifically neutralize HSV-1 infection in vitro via HVEM. Furthermore, we showed for the first time that HVEM-specific HSV-1 neutralizing antibodies protect mice from HSV-1 eye disease, indicating the critical role of HVEM in HSV-1 ocular infection., (Copyright © 2017 American Society for Microbiology.)
- Published
- 2017
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43. V1V2-specific complement activating serum IgG as a correlate of reduced HIV-1 infection risk in RV144.
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Perez LG, Martinez DR, deCamp AC, Pinter A, Berman PW, Francis D, Sinangil F, Lee C, Greene K, Gao H, Nitayaphan S, Rerks-Ngarm S, Kaewkungwal J, Pitisuttithum P, Tartaglia J, O'Connell RJ, Robb ML, Michael NL, Kim JH, Gilbert P, and Montefiori DC
- Subjects
- AIDS Vaccines immunology, Amino Acid Sequence, Antibodies, Monoclonal immunology, Antibodies, Neutralizing immunology, HIV Envelope Protein gp120 immunology, HIV-1, Humans, AIDS Vaccines administration & dosage, Complement Activation, HIV Infections immunology, Immunoglobulin G blood
- Abstract
Non-neutralizing IgG to the V1V2 loop of HIV-1 gp120 correlates with a decreased risk of HIV-1 infection but the mechanism of protection remains unknown. This V1V2 IgG correlate was identified in RV144 Thai trial vaccine recipients, who were primed with a canarypox vector expressing membrane-bound gp120 (vCP1521) and boosted with vCP1521 plus a mixture gp120 proteins from clade B and clade CRF01_AE (B/E gp120). We sought to determine whether the mechanism of vaccine protection might involve antibody-dependent complement activation. Complement activation was measured as a function of complement component C3d deposition on V1V2-coated beads in the presence of RV144 sera. Variable levels of complement activation were detected two weeks post final boosting in RV144, which is when the V1V2 IgG correlate was identified. The magnitude of complement activation correlated with V1V2-specific serum IgG and was stronger and more common in RV144 than in HIV-1 infected individuals and two related HIV-1 vaccine trials, VAX003 and VAX004, where no protection was seen. After adjusting for gp120 IgA, V1V2 IgG, gender, and risk score, complement activation by case-control plasmas from RV144 correlated inversely with a reduced risk of HIV-1 infection, with odds ratio for positive versus negative response to TH023-V1V2 0.42 (95% CI 0.18 to 0.99, p = 0.048) and to A244-V1V2 0.49 (95% CI 0.21 to 1.10, p = 0.085). These results suggest that complement activity may have contributed in part to modest protection against the acquisition of HIV-1 infection seen in the RV144 trial.
- Published
- 2017
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44. Antibody to HSV gD peptide induced by vaccination does not protect against HSV-2 infection in HSV-2 seronegative women.
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Gilbert PB, Excler JL, Tomaras GD, Carpp LN, Haynes BF, Liao HX, Montefiori DC, Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, Kaewkungwal J, Kijak GH, Tovanabutra S, Francis DP, Lee C, Sinangil F, Berman PW, Premsri N, Kunasol P, O'Connell RJ, Michael NL, Robb ML, Morrow R, Corey L, and Kim JH
- Subjects
- AIDS Vaccines administration & dosage, Adult, Female, HIV Antibodies administration & dosage, HIV Envelope Protein gp120 genetics, HIV Envelope Protein gp120 immunology, HIV Infections immunology, HIV Infections virology, HIV-1 immunology, HIV-1 pathogenicity, Herpes Simplex genetics, Herpes Simplex immunology, Herpes Simplex virology, Herpesvirus 1, Human immunology, Herpesvirus 1, Human pathogenicity, Herpesvirus 2, Human immunology, Herpesvirus 2, Human pathogenicity, Humans, Immunoglobulin A immunology, Immunoglobulin G immunology, Male, Vaccines, Synthetic administration & dosage, Vaccines, Synthetic immunology, Viral Envelope Proteins genetics, Viral Envelope Proteins immunology, AIDS Vaccines immunology, HIV Antibodies immunology, HIV Infections prevention & control, Herpes Simplex prevention & control
- Abstract
Background: In the HIV-1 vaccine trial RV144, ALVAC-HIV prime with an AIDSVAX® B/E boost reduced HIV-1 acquisition by 31% at 42 months post first vaccination. The bivalent AIDSVAX® B/E vaccine contains two gp120 envelope glycoproteins, one from the subtype B HIV-1 MN isolate and one from the subtype CRF01_AE A244 isolate. Each envelope glycoprotein harbors a highly conserved 27-amino acid HSV-1 glycoprotein D (gD) tag sequence that shares 93% sequence identity with the HSV-2 gD sequence. We assessed whether vaccine-induced anti-gD antibodies protected females against HSV-2 acquisition in RV144., Methods: Of the women enrolled in RV144, 777 vaccine and 807 placebo recipients were eligible and randomly selected according to their pre-vaccination HSV-1 and HSV-2 serostatus for analysis. Immunoglobulin G (IgG) and IgA responses to gD were determined by a binding antibody multiplex assay and HSV-2 serostatus was determined by Western blot analysis. Ninety-three percent and 75% of the vaccine recipients had anti-gD IgG and IgA responses two weeks post last vaccination, respectively. There was no evidence of reduction in HSV-2 infection by vaccination compared to placebo recipients over 78 weeks of follow-up. The annual incidence of HSV-2 infection in individuals who were HSV-2 negative at baseline or HSV-1 positive and HSV-2 indeterminate at baseline were 4.38/100 person-years (py) and 3.28/100 py in the vaccine and placebo groups, respectively. Baseline HSV-1 status did not affect subsequent HSV-2 acquisition. Specifically, the estimated odds ratio of HSV-2 infection by Week 78 for female placebo recipients who were baseline HSV-1 positive (n = 422) vs. negative (n = 1120) was 1.14 [95% confidence interval 0.66 to 1.94, p = 0.64)]. No evidence of reduction in the incidence of HSV-2 infection by vaccination was detected., Conclusions: AIDSVAX® B/E containing gD did not confer protection from HSV-2 acquisition in HSV-2 seronegative women, despite eliciting anti-gD serum antibodies.
- Published
- 2017
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45. A novel mechanism linking memory stem cells with innate immunity in protection against HIV-1 infection.
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Wang Y, Whittall T, Neil S, Britton G, Mistry M, Rerks-Ngarm S, Pitisuttithum P, Kaewkungwal J, Nitayaphan S, Yu X, Sato A, O'Connell RJ, Michael NL, Robb ML, Kim JH, and Lehner T
- Subjects
- AIDS Vaccines administration & dosage, HIV Infections immunology, Humans, AIDS Vaccines immunology, CD4-Positive T-Lymphocytes immunology, HIV Infections prevention & control, HIV-1 immunology, Immunity, Innate, Immunologic Memory, Stem Cells physiology
- Abstract
HIV infection affects 37 million people and about 1.7 million are infected annually. Among the phase III clinical trials only the RV144 vaccine trial elicited significant protection against HIV-1 acquisition, but the efficacy and immune memory were inadequate. To boost these vaccine functions we studied T stem cell memory (TSCM) and innate immunity. TSCM cells were identified by phenotypic markers of CD4
+ T cells and they were further characterised into 4 subsets. These expressed the common IL-2/IL-15 receptors and another subset of APOBEC3G anti-viral restriction factors, both of which were upregulated. In contrast, CD4+ TSCM cells expressing CCR5 co-receptors and α4β7 mucosal homing integrins were decreased. A parallel increase in CD4+ T cells was recorded with IL-15 receptors, APOBEC3G and CC chemokines, the latter downmodulating CCR5 molecules. We suggest a novel mechanism of dual memory stem cells; the established sequential memory pathway, TSCM →Central →Effector memory CD4+ T cells and the innate pathway consisting of the 4 subsets of TSCM. Both pathways are likely to be activated by endogenous HSP70. The TSCM memory stem cell and innate immunity pathways have to be optimised to boost the efficacy and immune memory of protection against HIV-1 in the clinical trial.- Published
- 2017
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46. Boosting of HIV envelope CD4 binding site antibodies with long variable heavy third complementarity determining region in the randomized double blind RV305 HIV-1 vaccine trial.
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Easterhoff D, Moody MA, Fera D, Cheng H, Ackerman M, Wiehe K, Saunders KO, Pollara J, Vandergrift N, Parks R, Kim J, Michael NL, O'Connell RJ, Excler JL, Robb ML, Vasan S, Rerks-Ngarm S, Kaewkungwal J, Pitisuttithum P, Nitayaphan S, Sinangil F, Tartaglia J, Phogat S, Kepler TB, Alam SM, Liao HX, Ferrari G, Seaman MS, Montefiori DC, Tomaras GD, Harrison SC, and Haynes BF
- Subjects
- AIDS Vaccines immunology, Cell Separation, Complementarity Determining Regions immunology, Crystallography, X-Ray, Double-Blind Method, HIV Envelope Protein gp120 immunology, HIV Infections immunology, HIV-1 immunology, Humans, Image Processing, Computer-Assisted, Microscopy, Electron, Neutralization Tests, Polymerase Chain Reaction, Surface Plasmon Resonance, AIDS Vaccines administration & dosage, CD4 Antigens immunology, HIV Antibodies immunology, HIV Infections prevention & control, Immunization, Secondary methods
- Abstract
The canary pox vector and gp120 vaccine (ALVAC-HIV and AIDSVAX B/E gp120) in the RV144 HIV-1 vaccine trial conferred an estimated 31% vaccine efficacy. Although the vaccine Env AE.A244 gp120 is antigenic for the unmutated common ancestor of V1V2 broadly neutralizing antibody (bnAbs), no plasma bnAb activity was induced. The RV305 (NCT01435135) HIV-1 clinical trial was a placebo-controlled randomized double-blinded study that assessed the safety and efficacy of vaccine boosting on B cell repertoires. HIV-1-uninfected RV144 vaccine recipients were reimmunized 6-8 years later with AIDSVAX B/E gp120 alone, ALVAC-HIV alone, or a combination of ALVAC-HIV and AIDSVAX B/E gp120 in the RV305 trial. Env-specific post-RV144 and RV305 boost memory B cell VH mutation frequencies increased from 2.9% post-RV144 to 6.7% post-RV305. The vaccine was well tolerated with no adverse events reports. While post-boost plasma did not have bnAb activity, the vaccine boosts expanded a pool of envelope CD4 binding site (bs)-reactive memory B cells with long third heavy chain complementarity determining regions (HCDR3) whose germline precursors and affinity matured B cell clonal lineage members neutralized the HIV-1 CRF01 AE tier 2 (difficult to neutralize) primary isolate, CNE8. Electron microscopy of two of these antibodies bound with near-native gp140 trimers showed that they recognized an open conformation of the Env trimer. Although late boosting of RV144 vaccinees expanded a novel pool of neutralizing B cell clonal lineages, we hypothesize that boosts with stably closed trimers would be necessary to elicit antibodies with greater breadth of tier 2 HIV-1 strains., Trial Registration: ClinicalTrials.gov NCT01435135.
- Published
- 2017
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47. Tissue memory B cell repertoire analysis after ALVAC/AIDSVAX B/E gp120 immunization of rhesus macaques.
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Luo K, Liao HX, Zhang R, Easterhoff D, Wiehe K, Gurley TC, Armand LC, Allen AA, Von Holle TA, Marshall DJ, Whitesides JF, Pritchett J, Foulger A, Hernandez G, Parks R, Lloyd KE, Stolarchuk C, Sawant S, Peel J, Yates NL, Dunford E, Arora S, Wang A, Bowman CM, Sutherland LL, Scearce RM, Xia SM, Bonsignori M, Pollara J, Edwards RW, Santra S, Letvin NL, Tartaglia J, Francis D, Sinangil F, Lee C, Kaewkungwal J, Nitayaphan S, Pitisuttithum P, Rerks-Ngarm S, Michael NL, Kim JH, Alam SM, Vandergrift NA, Ferrari G, Montefiori DC, Tomaras GD, Haynes BF, and Moody MA
- Subjects
- Animals, HIV Antibodies analysis, HIV Envelope Protein gp120 administration & dosage, Immunization, Secondary, Immunoglobulin G analysis, Macaca mulatta, AIDS Vaccines immunology, B-Lymphocytes classification, HIV Envelope Protein gp120 immunology, HIV Infections prevention & control, Immunity, Mucosal
- Abstract
The ALVAC prime/ALVAC + AIDSVAX B/E boost RV144 vaccine trial induced an estimated 31% efficacy in a low-risk cohort where HIV‑1 exposures were likely at mucosal surfaces. An immune correlates study demonstrated that antibodies targeting the V2 region and in a secondary analysis antibody-dependent cellular cytotoxicity (ADCC), in the presence of low envelope-specific (Env-specific) IgA, correlated with decreased risk of infection. Thus, understanding the B cell repertoires induced by this vaccine in systemic and mucosal compartments are key to understanding the potential protective mechanisms of this vaccine regimen. We immunized rhesus macaques with the ALVAC/AIDSVAX B/E gp120 vaccine regimen given in RV144, and then gave a boost 6 months later, after which the animals were necropsied. We isolated systemic and intestinal vaccine Env-specific memory B cells. Whereas Env-specific B cell clonal lineages were shared between spleen, draining inguinal, anterior pelvic, posterior pelvic, and periaortic lymph nodes, members of Env‑specific B cell clonal lineages were absent in the terminal ileum. Env‑specific antibodies were detectable in rectal fluids, suggesting that IgG antibodies present at mucosal sites were likely systemically produced and transported to intestinal mucosal sites., Competing Interests: J. Tartaglia was an employee of Sanofi and D. Francis, F. Sinangil, and C. Lee were employees of Global Solutions for Infectious Diseases at the time this study was performed. D. Francis, F. Sinangil, and C. Lee are former employees of VaxGen.
- Published
- 2016
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48. Neutralization Takes Precedence Over IgG or IgA Isotype-related Functions in Mucosal HIV-1 Antibody-mediated Protection.
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Astronomo RD, Santra S, Ballweber-Fleming L, Westerberg KG, Mach L, Hensley-McBain T, Sutherland L, Mildenberg B, Morton G, Yates NL, Mize GJ, Pollara J, Hladik F, Ochsenbauer C, Denny TN, Warrier R, Rerks-Ngarm S, Pitisuttithum P, Nitayapan S, Kaewkungwal J, Ferrari G, Shaw GM, Xia SM, Liao HX, Montefiori DC, Tomaras GD, Haynes BF, and McElrath JM
- Subjects
- Animals, Antibodies, Neutralizing immunology, Biomarkers, Disease Models, Animal, Female, HIV Infections prevention & control, HIV Infections virology, HIV-1 genetics, Humans, Immunity, Mucosal, Immunophenotyping, Leukocytes immunology, Leukocytes metabolism, Macaca mulatta, Mucous Membrane virology, Neutralization Tests, Simian Acquired Immunodeficiency Syndrome immunology, Simian Acquired Immunodeficiency Syndrome prevention & control, Simian Acquired Immunodeficiency Syndrome virology, Simian Immunodeficiency Virus immunology, Vagina immunology, Vagina virology, HIV Antibodies immunology, HIV Infections immunology, HIV-1 immunology, Immunoglobulin A immunology, Immunoglobulin G immunology, Mucous Membrane immunology
- Abstract
HIV-1 infection occurs primarily through mucosal transmission. Application of biologically relevant mucosal models can advance understanding of the functional properties of antibodies that mediate HIV protection, thereby guiding antibody-based vaccine development. Here, we employed a human ex vivo vaginal HIV-1 infection model and a rhesus macaque in vivo intrarectal SHIV challenge model to probe the protective capacity of monoclonal broadly-neutralizing (bnAb) and non-neutralizing Abs (nnAbs) that were functionally modified by isotype switching. For human vaginal explants, we developed a replication-competent, secreted NanoLuc reporter virus system and showed that CD4 binding site bnAbs b12 IgG1 and CH31 IgG1 and IgA2 isoforms potently blocked HIV-1
JR-CSF and HIV-1Bal26 infection. However, IgG1 and IgA nnAbs, either alone or together, did not inhibit infection despite the presence of FcR-expressing effector cells in the tissue. In macaques, the CH31 IgG1 and IgA2 isoforms infused before high-dose SHIV challenge were completely to partially protective, respectively, while nnAbs (CH54 IgG1 and CH38 mIgA2) were non-protective. Importantly, in both mucosal models IgG1 isotype bnAbs were more protective than the IgA2 isotypes, attributable in part to greater neutralization activity of the IgG1 variants. These findings underscore the importance of potent bnAb induction as a primary goal of HIV-1 vaccine development., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)- Published
- 2016
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49. Identification of New Regions in HIV-1 gp120 Variable 2 and 3 Loops that Bind to α4β7 Integrin Receptor.
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Peachman KK, Karasavvas N, Chenine AL, McLinden R, Rerks-Ngarm S, Jaranit K, Nitayaphan S, Pitisuttithum P, Tovanabutra S, Zolla-Pazner S, Michael NL, Kim JH, Alving CR, and Rao M
- Subjects
- Amino Acid Sequence, Antibodies, Monoclonal immunology, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism, Case-Control Studies, Cell Line, HIV Antibodies immunology, HIV Envelope Protein gp120 immunology, HIV Infections immunology, HIV-1 immunology, HIV-1 metabolism, Humans, Immunoglobulin G immunology, Immunoglobulin G metabolism, Integrins immunology, Molecular Sequence Data, Neutralization Tests methods, HIV Envelope Protein gp120 metabolism, HIV Infections metabolism, Integrins metabolism, Protein Binding immunology
- Abstract
Background: The gut mucosal homing integrin receptor α4β7 present on activated CD4+ T cells interacts with the HIV-1 gp120 second variable loop (V2). Case control analysis of the RV144 phase III vaccine trial demonstrated that plasma IgG binding antibodies specific to scaffolded proteins expressing the first and second variable regions (V1V2) of HIV envelope protein gp120 containing the α4β7 binding motif correlated inversely with risk of infection. Subsequently antibodies to the V3 region were also shown to correlate with protection. The integrin receptor α4β7 was shown to interact with the LDI/V motif on V2 loop but recent studies suggest that additional regions of V2 loop could interact with the α4β7. Thus, there may be several regions on the V2 and possibly V3 loops that may be involved in this binding. Using a cell line, that constitutively expressed α4β7 receptors but lacked CD4, we examined the contribution of V2 and V3 loops and the ability of V2 peptide-, V2 integrin-, V3-specific monoclonal antibodies (mAbs), and purified IgG from RV144 vaccinees to block the V2/V3-α4β7 interaction., Results: We demonstrate that α4β7 on RPMI8866 cells bound specifically to its natural ligand mucosal addressin cell adhesion molecule-1 (MAdCAM-1) as well as to cyclic-V2 and cyclic-V3 peptides. This binding was inhibited by anti-α4β7-specific monoclonal antibody (mAb) ACT-1, mAbs specific to either V2 or V3 loops, and by purified primary virions or infectious molecular clones expressing envelopes from acute or chronic subtypes A, C, and CRF01_AE viruses. Plasma from HIV-1 infected Thai individuals as well as purified IgG from uninfected RV144 vaccinees inhibited (0-50%) the binding of V2 and V3 peptides to α4β7., Conclusion: Our results indicate that in addition to the tripeptide LDI/V motif, other regions of the V2 and V3 loops of gp120 were involved in binding to α4β7 receptors and this interaction was blocked by anti-V2 peptide, anti-V2 integrin, and anti-V3 antibodies. The ability of purified IgG from some of the uninfected RV144 vaccinees to inhibit α4β7 raises the hypothesis that anti-V2 and anti-V3 antibodies may play a role in blocking the gp120-α4β7 interaction after vaccination and thus prevent HIV-1 acquisition.
- Published
- 2015
- Full Text
- View/download PDF
50. HIV-1 infections with multiple founders are associated with higher viral loads than infections with single founders.
- Author
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Janes H, Herbeck JT, Tovanabutra S, Thomas R, Frahm N, Duerr A, Hural J, Corey L, Self SG, Buchbinder SP, McElrath MJ, O'Connell RJ, Paris RM, Rerks-Ngarm S, Nitayaphan S, Pitisuttihum P, Kaewkungwal J, Robb ML, Michael NL, Mullins JI, Kim JH, Gilbert PB, and Rolland M
- Subjects
- HIV Infections virology, Humans, Founder Effect, HIV Infections genetics, HIV-1 isolation & purification, Viral Load
- Abstract
Given the variation in the HIV-1 viral load (VL) set point across subjects, as opposed to a fairly stable VL over time within an infected individual, it is important to identify the characteristics of the host and virus that affect VL set point. Although recently infected individuals with multiple phylogenetically linked HIV-1 founder variants represent a minority of HIV-1 infections, we found--n two different cohorts--hat more diverse HIV-1 populations in early infection were associated with significantly higher VL 1 year after HIV-1 diagnosis.
- Published
- 2015
- Full Text
- View/download PDF
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