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Background: Although previous studies have demonstrated that antigen valency is important to diversify the B cell repertoire, the ability of multivalent HIV vaccines to increase the breadth of vaccine-elicited antibodies and to promote neutralization remain unclear. Herein, we utilized a novel nanomaterial platform (Q11) to evaluate the influence of antigen valency on the HIV vaccine-elicited antibody responses. Methods: Self-assembly of the fiber-like nanoscale structure of Q11 was triggered by increasing the solvent ionic strength, followed by conjugation of HIV Envelope gycoprotein120 of clade C strains. We constructed vaccines with distinct valency by changing the concentration of antigen in the conjugation. Mice and rabbits were immunized with 15 [micro]g of gp120 or Q11-conjugated gp120 vaccine (gp120-Q11) along with a TLR7/8 and 9 agonist adjuvant STR8SC. A bead-based multiplex assay was used to measure antibody binding to heterologous Envs of subtypes B, C, and CRF_AE, and the TZM-bl cell assay was used to measure neutralization. Results: Mice immunized with gp120-Q11 demonstrated higher antibody titers against the autologous Env (p =0.027) after three immunizations; and higher binding to the 4 heterologous Env after each immunization than mice immunized with gp120 (Figure 1). The increased magnitude and breadth were only observed in mice immunized gp120-Q11 with 3 to 4 antigens on each fiber but not with gp120-Q11 with lower valency, suggesting that multivalent antigen presentation on Q11 contributed to the enhanced response. Immunization of rabbits indicated that Q11-gp120 also induced higher neutralization titer against the autologous tier 1 virus than gp120 (p =0.0285). Conclusions: We demonstrated that increasing the antigen valency by Q11 conjugation enhanced the humoral response in two distinct animal models, showing the potential of such nanomaterial in vaccine delivery. As a more clinically relevant model is required to further assess this platform, we plan to conjugate SOSIP trimer to Q11 and assess its immunogenicity in non-human primates., OA18.05LB J.-L. Chen (1); C. Fries (2); M. Dennis (3); J. Eudailey (3); A. Moody (3); S. Permar (3); J. Collier (2) and G. Fouda (3) (1) Duke University, Molecular [...]

Abstract Background Breastfeeding is a leading cause of infant HIV-1 infection in the developing world, yet only a minority of infants exposed to HIV-1 via breastfeeding become infected. As a genetic bottleneck severely restricts the number of postnatally-transmitted variants, genetic or phenotypic properties of the virus Envelope (Env) could be important for the establishment of infant infection. We examined the efficiency of virologic functions required for initiation of infection in the gastrointestinal tract and the neutralization sensitivity of HIV-1 Env variants isolated from milk of three postnatally-transmitting mothers (n=13 viruses), five clinically-matched nontransmitting mothers (n=16 viruses), and seven postnatally-infected infants (n = 7 postnatally-transmitted/founder (T/F) viruses). Results There was no difference in the efficiency of epithelial cell interactions between Env virus variants from the breast milk of transmitting and nontransmitting mothers. Moreover, there was similar efficiency of DC-mediated trans-infection, CCR5-usage, target cell fusion, and infectivity between HIV-1 Env-pseudoviruses from nontransmitting mothers and postnatal T/F viruses. Milk Env-pseudoviruses were generally sensitive to neutralization by autologous maternal plasma and resistant to breast milk neutralization. Infant T/F Env-pseudoviruses were equally sensitive to neutralization by broadly-neutralizing monoclonal and polyclonal antibodies as compared to nontransmitted breast milk Env variants. Conclusion Postnatally-T/F Env variants do not appear to possess a superior ability to interact with and cross a mucosal barrier or an exceptional resistance to neutralization that define their capability to initiate infection across the infant gastrointestinal tract in the setting of preexisting maternal antibodies.

Many adolescents under 18 years old who sell sex are at elevated risk for sexually transmitted infection (STI) acquisition, which may persist into adulthood. There has been limited study of the burden of the risks and vulnerabilities among women who started selling sex as adolescents across Sub-Saharan Africa. In this study, a Adult female sex workers (FSW) recruited through respondent-driven sampling in five cities in Cameroon from December 2015 to October 2016 completed a questionnaire and human immunodeficiency virus (HIV) and syphilis testing. Multivariable logistic regression analysis controlling for age was used to identify factors associated with reporting selling sex before age 18. Selling sex before age 18 was reported by 11.5% (256/2,220) of FSW. Initiation of selling sex as an adolescent was positively associated with experiencing dysuria (adjusted odds ratio [aOR]:1.50, 95% confidence interval [CI]:1.08-2.10) or genital warts (aOR:1.78, 95% CI:1.08-2.94) and negatively associated with prior recent testing for HIV (aOR:0.71, 95% CI:0.53-0.96) or STIs (aOR:0.65, 95% CI:0.44-0.96). Consistent condom use with clients was negatively associated with early initiation of selling sex (aOR:0.58, 95% CI:0.42-0.80), while experience of recent sexual violence was positively associated with early initiation (aOR:1.74, 95% CI:1.15-2.63). There were no independent significant differences in HIV (24.5%) or syphilis (8.3%) prevalence. Given the limited use of HIV and STI testing services by women who sold sex as adolescents, the prevalence of forced sex, condomless sex, and STI symptoms were high. Programs serving FSW should more vigorously aim to serve adolescents and adults who began selling sex early., (© 2023. The Author(s).)

The Delta pandemic wave saw increased maternal morbidity and mortality compared to prior viral strains. COVID-19 vaccination in pregnancy elicits detectable levels of neutralizing antibodies to SARS-CoV-2 wild type and SARS-CoV-2 Delta variants in both maternal and neonatal samples at delivery. Our results demonstrate the effectiveness of vaccination which confers an immunological response against newer, and potentially more dangerous, viral variants., (Copyright © 2023 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

The U.S. Food and Drug Administration only gave emergency use authorization of the BNT162b2 and mRNA-1273 SARS-CoV-2 vaccines for infants 6 months and older in June 2022. Yet questions regarding the durability of vaccine efficacy, especially against emerging variants, in this age group remain. We demonstrated previously that a two-dose regimen of stabilized prefusion Washington SARS-CoV-2 S-2P spike (S) protein encoded by mRNA encapsulated in lipid nanoparticles (mRNA-LNP) or purified S-2P mixed with 3M-052, a synthetic Toll-like receptor (TLR) 7/8 agonist, in a squalene emulsion (Protein+3M-052-SE) was safe and immunogenic in infant rhesus macaques. Here, we demonstrate that broadly neutralizing and spike-binding antibodies against variants of concern (VOCs), as well as T cell responses, persisted for 12 months. At 1 year, corresponding to human toddler age, we challenged vaccinated rhesus macaques and age-matched nonvaccinated controls intranasally and intratracheally with a high dose of heterologous SARS-CoV-2 B.1.617.2 (Delta). Seven of eight control rhesus macaques exhibited severe interstitial pneumonia and high virus replication in the upper and lower respiratory tract. In contrast, vaccinated rhesus macaques had faster viral clearance with mild to no pneumonia. Neutralizing and binding antibody responses to the B.1.617.2 variant at the day of challenge correlated with lung pathology and reduced virus replication. Overall, the Protein+3M-052-SE vaccine provided superior protection to the mRNA-LNP vaccine, emphasizing opportunities for optimization of current vaccine platforms. The observed efficacy of both vaccines 1 year after vaccination supports the implementation of an early-life SARS-CoV-2 vaccine.

A better understanding of the impact of early innate immune responses after vaccine priming on vaccine-elicited adaptive immune responses could inform rational design for effective HIV vaccines. The current study compared the whole blood molecular immune signatures of a 3M-052-SE adjuvanted HIV Env protein vaccine to a regimen combining the adjuvanted Env protein with simultaneous administration of a modified Vaccinia Ankara vector expressing HIV Env in infant rhesus macaques at days 0, 1, and 3 post vaccine prime. Both vaccines induced a rapid innate response, evident by elevated inflammatory plasma cytokines and altered gene expression. We identified 25 differentially-expressed genes (DEG) on day 1 compared to day 0 in the HIV protein vaccine group. In contrast, in the group that received both the Env protein and the MVA-Env vaccine only two DEG were identified, implying that the MVA-Env modified the innate response to the adjuvanted protein vaccine. By day 3, only three DEG maintained altered expression, indicative of the transient nature of the innate response. The DEG represented immune pathways associated with complement activation, type I interferon and interleukin signaling, pathogen sensing, and induction of adaptive immunity. DEG expression on day 1 was correlated to Env-specific antibody responses, in particular antibody-dependent cytotoxicity responses at week 34, and Env-specific follicular T helper cells. Results from network analysis supported the interaction of DEG and their proteins in B cell activation. These results emphasize that vaccine-induced HIV-specific antibody responses can be optimized through the modulation of the innate response to the vaccine prime., Competing Interests: Author MT was employed by the company 3M Corporate Research Materials Laboratory. The remaining 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 Vijayan, Cross, Curtis, Van Rompay, Pollara, Fox, Tomai, Hanke, Fouda, Hudgens, Permar and De Paris.)

Gender-based violence (GBV) is that perpetrated based on sex, gender identity, or perceived adherence to socially defined gender norms. This human rights violation is disproportionately experienced by HIV key populations including female sex workers (FSW), people who inject drugs (PWID), and men who have sex with men (MSM). Consequently, addressing GBV is a global priority in HIV response. There is limited consensus about optimal interventions and little known about effectiveness. Our systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and was registered in International Prospective Register of Systematic Reviews. Peer-reviewed and non-peer-reviewed literature were searched for articles that described a GBV prevention or response intervention specifically for key populations including FSW, PWID, and MSM. Results were organized by level(s) of implementation and pillars of a comprehensive GBV response: prevention, survivor support, and accountability/justice. Of 4,287 articles following removal of duplicates, 32 unique interventions (21 FSW, seven PWID, and nine MSM, not mutually exclusive) met inclusion criteria, representing 13 countries. Multisectoral interventions blended empowerment, advocacy, and crisis response with reductions in violence. Individual-level interventions included violence screening and response services. Violence-related safety promotion and risk reduction counseling within HIV risk reduction programming reduced violence. Quantitative evaluations were limited. Violence prevention and response interventions for FSW, PWID, and MSM span individual, community, and multisectoral levels with evidence of promising practices at each level. The strongest evidence supported addressing violence in the context of sexually transmitted infection/HIV risk reduction. As interventions continue to emerge, the rigor of accompanying evaluations must simultaneously advance to enable clarity on the health and safety impact of GBV prevention and response programming.

The inclusion of infants in the SARS-CoV-2 vaccine roll-out is important to prevent severe complications of pediatric SARS-CoV-2 infections and to limit transmission and could possibly be implemented via the global pediatric vaccine schedule. However, age-dependent differences in immune function require careful evaluation of novel vaccines in the pediatric population. Toward this goal, we assessed the safety and immunogenicity of two SARS-CoV-2 vaccines. Two groups of 8 infant rhesus macaques (RMs) were immunized intramuscularly at weeks 0 and 4 with stabilized prefusion SARS-CoV-2 S-2P spike (S) protein encoded by mRNA encapsulated in lipid nanoparticles (mRNA-LNP) or the purified S protein mixed with 3M-052, a synthetic TLR7/8 agonist in a squalene emulsion (Protein+3M-052-SE). Neither vaccine induced adverse effects. Both vaccines elicited high magnitude IgG binding to RBD, N terminus domain, S1, and S2, ACE2 blocking activity, and high neutralizing antibody titers, all peaking at week 6. S-specific memory B cells were detected by week 4 and S-specific T cell responses were dominated by the production of IL-17, IFN-γ, or TNF-α. Antibody and cellular responses were stable through week 22. The immune responses for the mRNA-LNP vaccine were of a similar magnitude to those elicited by the Moderna mRNA-1273 vaccine in adults. The S-2P mRNA-LNP and Protein-3M-052-SE vaccines were well-tolerated and highly immunogenic in infant RMs, providing proof-of concept for a pediatric SARS-CoV-2 vaccine with the potential for durable immunity that might decrease the transmission of SARS-CoV-2 and mitigate the ongoing health and socioeconomic impacts of COVID-19., (Copyright © 2021, American Association for the Advancement of Science.)

Background: Epidemiological data are needed to characterize the age-specific HIV burden and engagement in HIV services among young, marginalized women in sub-Saharan Africa., Setting: Women aged ≥18 years who reported selling sex were recruited across 9 countries in Southern, Central, and West Africa through respondent driven sampling (N = 6592)., Methods: Individual-level data were pooled and age-specific HIV prevalence and antiretroviral therapy (ART) coverage were estimated for each region using generalized linear mixed models. HIV-service engagement outcomes (prior HIV testing, HIV status awareness, and ART use) were compared among women living with HIV across age strata (18-19, 20-24, and ≥25 years) using generalized estimating equations., Results: By age 18%-19%, 45.4% [95% confidence interval (CI): 37.9 to 53.0], 5.8% (95% CI: 4.3 to 7.8), and 4.0% (95% CI: 2.9 to 5.4) of young women who sell sex were living with HIV in Southern, Central, and West Africa respectively. Prevalence sharply increased during early adulthood in all regions, but ART coverage was suboptimal across age groups. Compared with adult women ≥25, young women aged 18-19 were less likely to have previously tested for HIV [prevalence ratio (PR) 0.76; 95% CI: 0.72 to 0.80], less likely to already be aware of their HIV status (PR 0.48; 95% CI: 0.35 to 0.64), and less likely to be taking ART (PR 0.67; 95% CI: 0.59 to 0.75)., Conclusions: HIV prevalence was already high by age 18-19 in this pooled analysis, demonstrating the need for prevention efforts that reach women who sell sex early in their adolescence. ART coverage remained low, with women in the youngest age group the least engaged in HIV-related services. Addressing barriers to HIV service delivery among young women who sell sex is central to a comprehensive HIV response.

Background: Female sex workers (FSWs) in Cameroon commonly have unmet need for contraception posing a high risk of unintended pregnancy. Unintended pregnancy leads to a range of outcomes, and due to legal restrictions, FSWs often seek unsafe abortions. Aside from the high burden of HIV, little is known about the broader sexual and reproductive health of FSWs in Cameroon., Methods: From December 2015 to October 2016, we recruited FSWs aged ≥18 years through respondent-driven sampling across 5 Cameroonian cities. Cross-sectional data were collected through a behavioral questionnaire. Modified-robust Poisson regression was used to approximate adjusted prevalence ratios (aPR) for TOP and current use of effective nonbarrier contraception., Results: Among 2,255 FSWs (median age 28 years), 57.6% reported history of unintended pregnancy and 40.0% reported prior TOP. In multivariable analysis, TOP history was associated with current nonbarrier contraceptive use (aPR=1.23, 95% confidence interval [CI]=1.07, 1.42); ever using emergency contraception (aPR=1.34, 95% CI=1.17, 1.55); >60 clients in the past month (aPR=1.29, 95% CI= 1.07, 1.54) compared to ≤30; inconsistent condom use with clients (aPR=1.17, 95% CI=1.00, 1.37); ever experiencing physical violence (aPR=1.24, 95% CI=1.09, 1.42); and older age. Most (76.5%) women used male condoms for contraception, but only 33.2% reported consistent condom use with all partners. Overall, 26.4% of women reported currently using a nonbarrier contraceptive method, and 6.2% reported using a long-acting method. Previous TOP (aPR=1.41, 95%CI=1.16, 1.72) and ever using emergency contraception (aPR=2.70, 95% CI=2.23, 3.26) were associated with higher nonbarrier contraceptive use. Recent receipt of HIV information (aPR=0.72, 95% CI=0.59, 0.89) and membership in an FSW community-based organization (aPR=0.73, 95% CI=0.57, 0.92) were associated with lower use nonbarrier contraceptive use., Conclusions: Experience of unintended pregnancies and TOP is common among FSWs in Cameroon. Given the low use of nonbarrier contraceptive methods and inconsistent condom use, FSWs are at risk of repeat unintended pregnancies. Improved integration of client-centered, voluntary family planning within community-led HIV services may better support the sexual and reproductive health and human rights of FSWs consistent with the United Nations Declaration of Human Rights., (© Bowring et al.)

Background: In general populations, consistent data highlight the relationships among violence, HIV risk behavior and depression; however, these patterns are not well understood among female sex workers (FSWs). We examined the relationship between FSWs' experiences with sexual violence and consistent condom use as a key HIV risk behavior and explored mental health as a potential mediator., Methods: In total, 2,165 FSWs were recruited via respondent-driven sampling in Cameroon in 2016. The women answered questions about violence, condom use and mental health., Results: Inconsistent condom use with clients was reported by 23.5% of participants (508/2,165). Lifetime sexual violence was prevalent with 33.0% (713/2,163) of participants. Almost 50% (1,067/2,143) of respondents had some level of depression. Sexual violence was significantly associated with inconsistent condom use (adjusted risk ratio (aRR) 1.4, 95% confidence interval (CI) (1.2-1.6)). Of FSWs with no depression, 24.9% (267/1,071) reported sexual violence, versus 56.1% (32/57) of respondents with severe depression ( p  < .01). Severe depression significantly increased risk of condomless sex (aRR 1.8, 95% CI (1.3-2.6)); in mediation analysis, both sexual violence and severe depression remained significant predictors of condomless sex (aRR 1.4, 95% CI (1.2, 1.6) and aRR 1.7, 95% CI (1.2-2.4), respectively). Depression did not mediate the relationship between sexual violence and condom use., Conclusion: Sexual violence and depression are prevalent and independently associated with condom nonuse with clients among FSWs in Cameroon. Results highlight the need for interventions to address mental health as well as gender-based violence for FSWs.

Background: In Cameroon, female sex workers (FSWs) and men who have sex with men (MSM) carry disproportionately high burdens of HIV. Despite specific vulnerabilities and health needs, young key populations remain understudied and underserved in Cameroon owing to legal, ethical, and social challenges. We aimed to assess and compare HIV-related behavioural and structural risks and coverage of HIV prevention and treatment services between young and older key populations to inform implementation strategies., Methods: FSWs and MSM aged 18 years or older were recruited through respondent-driven-sampling for a biobehavioural survey carried out in five Cameroonian cities. Prevalence of HIV, risk, stigma, and health service engagement were compared between young (18-24 years) and older (≥25 years) key populations. Multivariable Poisson regression models, disaggregated by key population, were constructed to estimate prevalence ratios (PR) by age group for HIV service engagement., Findings: Participants were recruited between Nov 30, 2015, and Oct 12, 2016. Among FSWs, 724 (32%) of 2255 were aged 18-24 years, and median age of first transactional or compensated sex was 22 years (IQR 19-28). Among MSM, 840 (63%) of 1323 were aged 18-24 years, and median age of first anal sex was 18 years (IQR 17-21). RDS-adjusted HIV prevalence was 8·5% (95% CI 4·7-15·2) among young FSWs and 12·9% (9·5-18·2) among young MSM. HIV viral suppression (<1000 copies per mL) was evident in 24 (43%) of 56 young and 292 (61%) of 479 older FSWs (p=0·0091) and 40 (34%) of 119 of young and 64 (42%) of 153 older MSM (p=0·17). Young FSWs were less likely than older FSWs to report recent peer education (PR 0·65, 95% CI 0·48-0·88), or membership of an FSW community-based organisation (PR 0·69, 0·55-0·86) and were more likely to report untreated sexually transmitted infection symptoms in the past year (PR 1·29, 1·03-1·61). Young MSM were less likely than older MSM to report an HIV test in the past year (PR 0·88, 0·78-0·98), recent peer education (PR 0·77, 0·62-0·95) and receipt of free condoms (PR 0·77, 0·67-0·89). By key population, condom use and recent experiences of stigma and violence were similar between age groups (p>0·05)., Interpretation: Young key populations have similar behavioural and structural risks to older populations but have lower coverage of HIV preventive and treatment services. Achieving an AIDS-free generation in Cameroon and elsewhere in the region necessitates overcoming social and legal challenges and delivering innovative, evidence-based, and human rights-affirming HIV prevention and treatment interventions for young key populations., Funding: PEPFAR, USAID., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Despite recent progress, there exist gaps in the prevention of vertical HIV transmission program access and uptake in Cameroon. Female sex workers (FSW), many of whom are mothers, are disproportionately affected by HIV and have specific barriers to HIV testing and treatment access. Testing for HIV-exposed infants is crucial in monitoring for incident infection and timely intervention. This study explores the level of early childhood testing and also associations between antenatal care (ANC) attendance and other factors and early childhood HIV testing among FSW in Cameroon., Methods: FSW were recruited to participate in an integrated biobehavioral survey in Cameroon between December 2015 and October 2016. Women were included in these analyses if they were living with HIV and had at least one living child. Both univariate and multivariable logistic regression were used to look at predictors of a child being tested for HIV before age five., Results: A total of 481/2255 FSW were eligible for these analyses as they were HIV seropositive and had at least one living child at the time of the study. Women included in these analyses had a median age of 35(IQR 30-41). Nearly 70% reported none of their children had been tested for HIV before age five (326/481), and 3.5%(17/481) reported one or more of their children had been diagnosed with HIV. ANC attendance (adjusted OR 2.12, 95% CI: [1.02, 4.55]), awareness of HIV status (aOR 3.70[2.30, 5.93]), pregnancy intentions (aOR 1.89[1.16, 3.08]), and higher education (aOR 2.17[1.01, 4.71]) were all independently associated with increased odds of women having a greater proportion of children tested for HIV before age five. Regional differences in early childhood testing were also observed., Conclusion: Vertical transmission of HIV remains a challenge in Cameroon, and HIV testing among children of FSW living with HIV was very low. ANC attendance and promotion of the mother's health were associated with increased child HIV testing. For women at high risk of HIV and for whom engagement in the health system is low, strategies to promote and ensure ANC attendance are essential for their health and the health of their children.

Background: Female sex workers (FSW) are disproportionately affected by HIV in Cameroon, with an estimated 23.6% HIV prevalence. Given the unavailability of HIV incidence data, to better understand associations with acquiring HIV we assessed the prevalence and associations with new HIV diagnoses among FSW in Cameroon., Methods: In 2016, FSW were recruited through respondent-driven sampling from 5 cities for a biobehavioral survey. Participants self-reporting living with HIV or with an indeterminate test status were excluded from analysis. New diagnoses were defined as testing HIV-positive when participants self-reported HIV-negative or unknown status. A multivariable modified Poisson regression model was developed to assess determinants of new HIV diagnosis (referent group: HIV-negative) using key covariates; adjusted prevalence ratios (aPR) are reported if statistically significant (P < 0.05)., Results: Overall 2255 FSW were recruited. Excluding participants who self-reported living with HIV (n = 297) and indeterminate test results (n = 7), 260/1951 (13.3%) FSW were newly diagnosed with HIV. Variables significantly associated with new HIV diagnosis were: no secondary/higher education [aPR: 1.56, 95% confidence interval (CI): 1.12 to 2.15], 5+ dependents compared with none (aPR: 2.11, 95% CI: 1.01 to 4.40), 5+ years involved in sex work compared with <1 year (aPR: 2.84, 95% CI: 1.26 to 6.42), history of incarceration (aPR: 2.13, 95% CI: 1.13 to 3.99), and low social capital (aPR: 1.53, 95% CI: 1.12 to 2.10). Higher monthly income (>250,000 FCFA vs. <50,000 FCFA) was associated with lower prevalence of new HIV diagnosis (aPR: 0.22, 95% CI: 0.05 to 0.86)., Conclusions: There are significant sociostructural factors that seem to potentiate risk of HIV infection and delay diagnosis among FSW in Cameroon. Initiatives to build social capital and integrate services such as pre-exposure prophylaxis and HIV self-testing into HIV programs may reduce new infections and decrease time to diagnosis and treatment.

Toward the goal of developing an effective HIV vaccine that can be administered in infancy to protect against postnatal and lifelong sexual HIV transmission risks, the current pilot study was designed to compare the effect of novel adjuvants on the induction of HIV Env-specific antibody responses in infant macaques. Aligning our studies with the adjuvanted proteins evaluated in a prime-boost schedule with ALVAC in the ongoing HVTN (HIV Vaccine Trials Network) 702 efficacy trial, we selected the bivalent clade C Env immunogens gp120 C.1086 and gp120 TV1 in combination with the MF59 adjuvant. However, we hypothesized that the adjuvant system AS01, that is included in the pediatric RTS,S malaria vaccine, would promote Env-specific antibody responses superior to those of the oil-in-water MF59 emulsion adjuvant. In a second study arm, we compared two emulsions, glucopyranosyl lipid adjuvant formulated in a stable emulsion (GLA-SE) and 3M-052-SE, containing Toll-like receptor 4 (TLR4) and TLR7/TLR8 (TLR7/8) ligand, respectively. The latter adjuvant had been previously demonstrated to be especially effective in activating neonatal antigen-presenting cells. Our results demonstrate that different adjuvants drive quantitatively or qualitatively distinct responses to the bivalent Env vaccine. AS01 induced higher Env-specific plasma IgG antibody levels than the antigen in MF59 and promoted improved antibody function in infants, and 3M-052-SE outperformed GLA-SE by inducing the highest breadth and functionality of antibody responses. Thus, distinct adjuvants are likely to be required for maximizing vaccine-elicited immune responses in infants, particularly when immunization in infancy aims to elicit both perinatal and lifelong immunity against challenging pathogens such as HIV. IMPORTANCE Alum remains the adjuvant of choice for pediatric vaccines. Yet the distinct nature of the developing immune system in infants likely requires novel adjuvants targeted specifically at the pediatric population to reach maximal vaccine efficacy with an acceptable safety profile. The current study supports the idea that additional adjuvants for pediatric vaccines should be, and need to be, tested in infants for their potential to enhance immune responses. Using an infant macaque model, our results suggest that both AS01 and 3M-052-SE can significantly improve and better sustain HIV Env-specific antibody responses than alum. Despite the limited number of animals, the results revealed interesting differences that warrant further testing of promising novel adjuvant candidates in larger preclinical and clinical studies to define the mechanisms leading to adjuvant-improved antibody responses and to identify targets for adjuvant and vaccine optimization., (Copyright © 2018 American Society for Microbiology.)

Tenascin-C (TNC) is a newly identified innate HIV-1-neutralizing protein present in breast milk, yet its presence and potential HIV-inhibitory function in other mucosal fluids is unknown. In this study, we identified TNC as a component of semen and cervical fluid of HIV-1-infected and uninfected individuals, although it is present at a significantly lower concentration and frequency compared to that of colostrum and mature breast milk, potentially due to genital fluid protease degradation. However, TNC was able to neutralize HIV-1 after exposure to low pH, suggesting that TNC could be active at low pH in the vaginal compartment. As mucosal fluids are complex and contain a number of proteins known to interact with the HIV-1 envelope, we further studied the relationship between the concentration of TNC and neutralizing activity in breast milk. The amount of TNC correlated only weakly with the overall innate HIV-1-neutralizing activity of breast milk of uninfected women and negatively correlated with neutralizing activity in milk of HIV-1 infected women, indicating that the amount of TNC in mucosal fluids is not adequate to impede HIV-1 transmission. Moreover, the presence of polyclonal IgG from milk of HIV-1 infected women, but not other HIV-1 envelope-binding milk proteins or monoclonal antibodies, blocked the neutralizing activity of TNC. Finally, as exogenous administration of TNC would be necessary for it to mediate measurable HIV-1 neutralizing activity in mucosal compartments, we established that recombinantly produced TNC has neutralizing activity against transmitted/founder HIV-1 strains that mimic that of purified TNC. Thus, we conclude that endogenous TNC concentration in mucosal fluids is likely inadequate to block HIV-1 transmission to uninfected individuals.

Sequestration of Plasmodium falciparum parasites within the placenta often leads to an accumulation of macrophages within the intervillous space and increased production of tumor necrosis factor alpha (TNF-alpha), a cytokine associated with placental pathology and poor pregnancy outcomes. P. falciparum glycosylphosphatidylinositol (GPI) anchors have been shown to be the major parasite component that induces TNF-alpha production by monocytes and macrophages. Antibodies against P. falciparum GPI (anti-PfGPI), however, can inhibit the induction of TNF-alpha and inflammation. Thus, the study was undertaken to determine whether anti-PfGPI antibodies down-regulate inflammatory-type changes in the placentas of women with malaria. Anti-PfGPI immunoglobulin M (IgM) and IgG levels were measured in 380 pregnant women with or without placental malaria, including those who delivered prematurely and at term. Results showed that anti-PfGPI antibody levels increased with gravidity and age and that malaria infection boosted anti-PfGPI antibodies in pregnant women. However, no association was found between anti-PfGPI antibodies and placental TNF-alpha levels or the presence of acute or chronic placental malaria. Furthermore, anti-PfGPI antibody levels were similar in women with preterm and full-term deliveries and were not associated with an increase in infant birth weight. Thus, these results fail to support a strong role for anti-PfGPI antibodies in the prevention of chronic placental malaria infections and malaria-associated poor birth outcomes.

Plasmodium falciparum-infected erythrocytes often are sequestered in the placenta and stimulate the accumulation of maternal mononuclear cells. In this study, the role that chemokines and cytokines play in mediating the inflammatory response was investigated. Placental parasites elicited a statistically significant increase in the levels of interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-10, in plasma collected from the intervillous space. Explants of fetal tissue from malaria-positive placentas also secreted significantly enhanced amounts of IFN-gamma. Culture supernatant of maternal intervillous leukocytes obtained from infected placentas contained significantly higher levels of TNF-alpha, IL-10, monocyte chemotactic protein-1, macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and IFN-gamma inducible protein-10 than did cultures of white blood cells obtained from uninfected placentas. Taken together, these results show that both fetal and maternal cells secrete inflammatory and immunoregulatory cytokines in response to P. falciparum and suggest that beta-chemokines produced by maternal cells contribute to the accumulation of macrophages in the intervillous space.