Search

[This corrects the article DOI: 10.1371/journal.ppat.1009101.].

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., Author summary The RV144 vaccine efficacy trial showed a reduction in HIV-1 infections that associated with binding antibody responses to the Envelope (Env) V1V2 loops but precise mechanisms remain unclear. To evaluate the effect of vaccine priming, we performed a systems serology analysis in 37 vaccine and 63 placebo recipients 6, 12 and 36 months after HIV-1 breakthrough infections. Vaccinees were characterized by strong V1V2-specific antibody responses synergized with V1V2-specific ADCP responses, whereas placebo recipients had stronger IgG3 and gp120-specific responses. The strongest distinguishing feature for vaccinees was IgG4 responses. RV144 vaccination enhanced Fc-mediated effector functions but limited the development of broadly neutralizing antibodies post-infection, which were found in eight placebo recipients but no vaccinee. These data show that RV144 vaccination primed B cells towards specific binding and functional antibody responses, with differences between groups still manifest three years after infection, i.e. on average five years after vaccination. These long-term consequences highlight that imprinting certain functions (while deterring other responses) could offer benefits even for leaky vaccines.

To estimate the proportion of vulvar and vaginal low-grade and high-grade squamous intraepithelial lesions (LSILs and HSILs) in females 15-26 years of age attributable to 14 human papillomavirus (HPV) genotypes (6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59).A post hoc analysis of prospectively diagnosed vulvar and vaginal LSILs and HSILs among females 15-26 years of age enrolled in the placebo arms of two phase 3, randomized HPV vaccine trials assessed 14 prespecified HPV genotypes associated with cervical cancers or anogenital warts using a type-specific multiplex polymerase chain reaction assay. The frequency of lesions associated with specific HPV genotypes was estimated by proportional and other attribution methods.During approximately 4 years of follow-up in 8,798 females, 40 vulvar LSILs and 46 vulvar HSILs were diagnosed in 68 females, and 118 vaginal LSILs and 33 vaginal HSILs were diagnosed in 107 females. Females developing vulvar (41.2%) or vaginal (49.5%) lesions also had cervical lesions, whereas 6.5% of females with cervical lesions had vaginal or vulvar lesions. At least 1 of the 14 HPV genotypes was detected in females with vulvar LSIL (72.5%), vulvar HSIL (91.3%), vaginal LSIL (61.9%), and vaginal HSIL (72.7%). Considering only HPV-positive lesions, the nine most common genotypes causing cervical cancer and anogenital warts (6, 11, 16, 18, 31, 33, 45, 52, and 58) were found in 89.4% of vulvar LSILs, 100% of vulvar HSILs, 56.0% of vaginal LSILs, and 78.3% of vaginal HSILs.Most vulvar and vaginal lesions were attributable to at least 1 of the 14 HPV genotypes analyzed. Effective immunization programs could potentially prevent substantial numbers of HPV-related vulvar and vaginal LSILs and HSILs.CLINICALTRIALS.GOV,: NCT00092521 and NCT00092534.

To evaluate the role of V3-specific IgG antibodies (Abs) in the RV144 clinical HIV vaccine trial, which reduced HIV-1 infection by 31.2%, the anti-V3 Ab response was assessed. Vaccinees' V3 Abs were highly cross-reactive with cyclic V3 peptides (cV3s) from diverse virus subtypes. Sieve analysis of CRF01_AE breakthrough viruses from 43 vaccine- and 66 placebo-recipients demonstrated an estimated vaccine efficacy of 85% against viruses with amino acids mismatching the vaccine at V3 site 317 (p = 0.004) and 52% against viruses matching the vaccine at V3 site 307 (p = 0.004). This analysis was supported by data showing that vaccinees' plasma Abs were less reactive with I307 when replaced with residues found more often in vaccinees' breakthrough viruses. Simultaneously, viruses with mutations at F317 were less infectious, possibly due to the contribution of F317 to optimal formation of the V3 hydrophobic core. These data suggest that RV144-induced V3-specific Abs imposed immune pressure on infecting viruses and inform efforts to design an HIV vaccine., Highlights • The RV144 vaccine reduced infection by viruses with isoleucine in V3 position 307. • Many vaccine-induced antibodies are cross-reactive and target an epitope including I307. • There was selection for breakthrough viruses carrying F317 in V3 (p = 0.004). • F317 is needed to maintain optimal infectivity. • F317 is a poor or non-contact residue for vaccine induced V3 antibodies.

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.

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.Objectives: The ability of HIV-1 vaccine candidates MRKAd5, VRC DNA/Ad5 and ALVAC/AIDSVAX to elicit CD8 + T cells with direct antiviral function was assessed and compared with HIV-1-infected volunteers. Design: Adenovirus serotype 5 (Ad5)-based regimens MRKAd5 and VRC DNA/Ad5, designed to elicit HIV-1-specific T cells, are immunogenic but failed to prevent infection or impact on viral loads in volunteers infected subsequently. Failure may be due in part to a lack of CD8 + T cells with effective antiviral functions. Methods: An in-vitro viral inhibition assay tested the ability of bispecific antibody expanded CD8 + T cells from peripheral blood mononuclear cells to inhibit replication of a multiclade panel of HIV-1 isolates in autologous CD4 + T cells. HIV-1 proteins recognized by CD8 + T cells were assessed by IFNγ enzyme-linked immunospot assay. Results: Ad5-based regimens elicited CD8 + T cells that inhibited replication of HIV-1 IIIB isolate with more limited inhibition of other isolates. IIIB isolate Gag and Pol genes have high sequence identities (>96%) to vector HIV-1 gene inserts, and these were the predominant HIV-1 proteins recognized by CD8 + T cells. Virus inhibition breadth was greater in antiretroviral naïve HIV-1-infected volunteers naturally controlling viremia (plasma viral load < 10 000/ml). HIV-1-inhibitory CD8 + T cells were not elicited by the ALVAC/AIDSVAX regimen. Conclusion: The Ad5-based regimens, although immunogenic, elicited CD8 + T cells with limited HIV-1-inhibition breadth. Effective T-cell-based vaccines should presumably elicit broader HIV-1-inhibition profiles. The viral inhibition assay can be used in vaccine design and to prioritize promising candidates with greater inhibition breadth for further clinical trials. ©

In the October 1, 2014 issue of this journal, Shmelkov et al. stated that “the immune-correlate analysis of the RV144 clinical trial revealed that human plasma IgA immune responses elicited by the RV144 vaccine correlated positively with a risk for HIV acquisition,” and inferred that this analysis supported vaccine-induced enhancement of HIV acquisition risk.1 This inference of vaccine-induced enhancement of HIV acquisition risk is incorrect, since the immune correlate analysis directly demonstrated that there was no vaccine-associated enhancement of infection risk in the trial.2 RV144 was a randomized, placebo-controlled Phase 3 clinical trial in Thailand testing the ability of the ALVAC-HIV (vCP1521) recombinant canarypox vector vaccine3 and AIDSVAX-B/E, a recombinant gp120 protein formulated in alum,4 to protect healthy heterosexual volunteers from HIV acquisition in comparison to placebo recipients. This was the only HIV vaccine efficacy trial to date to demonstrate any level of protection from HIV acquisition, as vaccine efficacy was estimated at 31.2% (95% CI 1.1 – 52.1; P = 0.04) at 3.5 y after enrollment in the modified intent-to-treat (mITT) analysis,5 and 60% (95% CI 22–80%) at one year after enrollment in a subsequent post hoc analysis.6 Haynes et al. published an analysis of immunologic correlates of risk of infection in vaccine recipients which demonstrated an inverse correlation between V1V2 antibody levels and the risk of infection (estimated odds ratio of infection per SD increase, 0.57; P = 0.02; estimated odds ratio for the highest versus lowest third of responders, 0.29; P = 0.02) and a direct correlation between plasma IgA antibody levels and the risk of infection (estimated odds ratio per SD increase, 1.54; P = 0.03; estimated odds ratio for the highest vs. lowest third of responders, 1.89; P = 0.17).2 However, because these analyses included the vaccine group only, they, by themselves, do not provide evidence for or against a vaccine-induced increase in the rate of HIV infection. Rather, to address that objective the HIV infection rate in the placebo group must be integrated into the analysis, as done by Haynes et al. and reported in Figure S3. That analysis demonstrated that neither low levels of V1V2 antibodies nor high levels of Env-specific IgA antibodies in vaccines were associated with higher rates of infection than were found among placebo recipients (estimated VE = 3.4%, 95% confidence interval −77% to 47% for lowest third V1V2 responders versus placebo; estimated VE = −5.4%, 95% confidence interval −87% to 40% for highest third IgA responders vs. placebo). Thus, this analysis failed to detect evidence for enhancement of infection, and do not support the claim by Shmelkov et al., “this result once again emphasized that HIV vaccines can potentially have adverse effects leading to enhancement of infection.” Rather, the most appropriate interpretation of the association of Env-specific IgA antibodies with HIV risk is that vaccine recipients with high IgA received no protection, due to IgA blocking and interference with effector functions of IgG that was indicated by the correlates of risk interaction analyses in Haynes et al.2 In particular, the interaction analyses supported that IgA inhibited antibody dependent cellular cytotoxicity (ADCC) protection, and follow-up research on the antibody repertoire of RV144 vaccines that isolated both natural IgG1 and IgA antibodies from vaccines directly demonstrated that IgA antibodies reacting with the same target epitopes on HIV envelope can indeed block IgG ADCC activity. Thus, there is now direct evidence that RV144 vaccine-induced IgA envelope antibodies have the capacity to block effector functions of IgG.7 RV144 remains the only trial of a candidate HIV vaccine regimen to demonstrate prevention of HIV acquisition. While protection from HIV infection in RV144 vaccines was correlated, both directly and inversely, with vaccine-induced antibody responses, there is no evidence that the vaccine regimen was associated with enhancement of infection.

The modest protection afforded by the RV144 vaccine offers an opportunity to evaluate its mechanisms of protection. Differences between HIV-1 breakthrough viruses from vaccine and placebo recipients can be attributed to the RV144 vaccine as this was a randomized and double-blinded trial. CD8 and CD4 T cell epitope repertoires were predicted in HIV-1 proteomes from 110 RV144 participants. Predicted Gag epitope repertoires were smaller in vaccine than in placebo recipients (p = 0.019). After comparing participant-derived epitopes to corresponding epitopes in the RV144 vaccine, the proportion of epitopes that could be matched differed depending on the protein conservation (only 36% of epitopes in Env vs 84-91% in Gag/Pol/Nef for CD8 predicted epitopes) or on vaccine insert subtype (55% against CRF01_AE vs 7% against subtype B). To compare predicted epitopes to the vaccine, we analyzed predicted binding affinity and evolutionary distance measurements. Comparisons between the vaccine and placebo arm did not reveal robust evidence for a T cell driven sieve effect, although some differences were noted in Env-V2 (0.022≤p-value≤0.231). The paucity of CD8 T cell responses identified following RV144 vaccination, with no evidence for V2 specificity, considered together both with the association of decreased infection risk in RV 144 participants with V-specific antibody responses and a V2 sieve effect, lead us to hypothesize that this sieve effect was not T cell specific. Overall, our results did not reveal a strong differential impact of vaccine-induced T cell responses among breakthrough infections in RV144 participants.