Antibody Fc effector functions and IgG3 associate with decreased HIV-1 risk.

HVTN 505 is a preventative vaccine efficacy trial testing DNA followed by recombinant adenovirus serotype 5 (rAd5) in circumcised, Ad5-seronegative men and transgendered persons who have sex with men in the United States. Identified immune correlates of lower HIV-1 risk and a virus sieve analysis revealed that, despite lacking overall efficacy, vaccine-elicited responses exerted pressure on infecting HIV-1 viruses. To interrogate the mechanism of the antibody correlate of HIV-1 risk, we examined antigen-specific antibody recruitment of Fcγ receptors (FcγRs), antibody-dependent cellular phagocytosis (ADCP), and the role of anti-envelope (anti-Env) IgG3. In a prespecified immune correlates analysis, antibody-dependent monocyte phagocytosis and antibody binding to FcγRIIa correlated with decreased HIV-1 risk. Follow-up analyses revealed that anti-Env IgG3 breadth correlated with reduced HIV-1 risk, anti-Env IgA negatively modified infection risk by Fc effector functions, and that vaccine recipients with a specific FcγRIIa single-nucleotide polymorphism locus had a stronger correlation with decreased HIV-1 risk when ADCP, Env-FcγRIIa, and IgG3 binding were high. Additionally, FcγRIIa engagement correlated with decreased viral load setpoint in vaccine recipients who acquired HIV-1. These data support a role for vaccine-elicited anti-HIV-1 Env IgG3, antibody engagement of FcRs, and phagocytosis as potential mechanisms for HIV-1 prevention.

Immune correlates of the Thai RV144 HIV vaccine regimen in South Africa.

One of the most successful HIV vaccines to date, the RV144 vaccine tested in Thailand, demonstrated correlates of protection including cross-clade V1V2 immunoglobulin G (IgG) breadth, Env-specific CD4+ T cell polyfunctionality, and antibody-dependent cellular cytotoxicity (ADCC) in vaccinees with low IgA binding. The HIV Vaccine Trials Network (HVTN) 097 trial evaluated this vaccine regimen in South Africa, where clade C HIV-1 predominates. We compared cellular and humoral responses at peak and durability immunogenicity time points in HVTN 097 and RV144 vaccinee samples, and evaluated vaccine-matched and cross-clade immune responses. At peak immunogenicity, HVTN 097 vaccinees exhibited significantly higher cellular and humoral immune responses than RV144 vaccinees. CD4+ T cell responses were more frequent in HVTN 097 irrespective of age and sex, and CD4+ T cell Env-specific functionality scores were higher in HVTN 097. Env-specific CD40L+ CD4+ T cells were more common in HVTN 097, with individuals having this pattern of expression demonstrating higher median antibody responses to HIV-1 Env. IgG and IgG3 binding antibody rates and response magnitude to gp120 vaccine- and V1V2 vaccine-matched antigens were higher or comparable in HVTN 097 than in RV144 ADCC, and ADCP functional antibody responses were elicited in HVTN 097. Env-specific IgG and CD4+ Env responses declined significantly over time in both trials. Overall, cross-clade immune responses associated with protection were better than expected in South Africa, suggesting wider applicability of this regimen.

Does per-act HIV-1 transmission risk through anal sex vary by gender? An updated systematic review and meta-analysis.

Quantifying HIV-1 transmission risk per-act of anal intercourse (AI) is important for HIV-1 prevention. We updated previous reviews by searching Medline and Embase to 02/2018. We derived pooled estimates of receptive AI (URAI) and insertive AI (UIAI) risk unprotected by condoms using random-effects models. Subgroup analyses were conducted by gender, study design, and whether antiretroviral treatment (ART) had been introduced by the time of the study. Two new relevant studies were identified, one of which met inclusion criteria, adding three new cohorts and increasing number of individuals/partnerships included from 1869 to 14 277. Four studies, all from high-income countries, were included. Pooled HIV-1 risk was higher for URAI (1.25%, 95% CI 0.55%-2.23%, N = 5, I2  = 87%) than UIAI (0.17%, 95 % CI 0.09%-0.26%, N = 3, I2  = 0%). The sole heterosexual URAI estimate (3.38%, 95% CI 1.85%-4.91%), from a study of 72 women published in a peer-reviewed journal, was significantly higher than the men-who-have-sex-with-men (MSM) pooled estimate (0.75%, 95% CI 0.56%-0.98%, N = 4, P < 0.0001) and higher than the only other heterosexual estimate identified (0.4%, 95% CI 0.08%-2.0%, based on 59 women, excluded for being a pre-2013 abstract). Pooled per-act URAI risk varied by study design (retrospective-partner studies: 2.56%, 95% CI 1.20%-4.42%, N = 2 (one MSM, one heterosexual); prospective studies: 0.71%, 95% CI 0.51%-0.93%, N = 3 MSM, P < 0.0001). URAI risk was lower for studies conducted in the ART era (0.75%, 95% CI 0.52%-1.03%) than pre-ART (1.67%, 95% CI 0.44%-3.67%) but not significantly so (P = 0.537). Prevention messages must emphasize that HIV-1 infectiousness through AI remains high, even in the ART era. Further studies, particularly among heterosexual populations and in resource-limited settings, are required to elucidate whether AI risk differs by gender, region and following population-level ART scale-up.

How common and frequent is heterosexual anal intercourse among South Africans? A systematic review and meta-analysis.

BACKGROUND: HIV is transmitted more effectively during anal intercourse (AI) than vaginal intercourse (VI). However, patterns of heterosexual AI practice and its contribution to South Africa's generalized epidemic remain unclear. We aimed to determine how common and frequent heterosexual AI is in South Africa. METHODS: We searched for studies reporting the proportion practising heterosexual AI (prevalence) and/or the number of AI and unprotected AI (UAI) acts (frequency) in South Africa from 1990 to 2015. Stratified random-effects meta-analysis by sub-groups was used to produce pooled estimates and assess the influence of participant and study characteristics on AI prevalence. We also estimated the fraction of all sex acts which were AI or UAI and compared condom use during VI and AI. RESULTS: Of 41 included studies, 31 reported on AI prevalence and 14 on frequency, over various recall periods. AI prevalence was high across different recall periods for sexually active general-risk populations (e.g. lifetime = 18.4% [95%CI:9.4-27.5%], three-month = 20.3% [6.1-34.7%]), but tended to be even higher in higher-risk populations such as STI patients and female sex workers (e.g. lifetime = 23.2% [0.0-47.4%], recall period not stated = 40.1% [36.2-44.0%]). Prevalence was higher in studies using more confidential interview methods. Among general and higher-risk populations, 1.2-40.0% and 0.7-21.0% of all unprotected sex acts were UAI, respectively. AI acts were as likely to be condom protected as vaginal acts. CONCLUSION: Reported heterosexual AI is common but variable among South Africans. Nationally and regionally representative sexual behaviour studies that use standardized recall periods and confidential interview methods, to aid comparison across studies and minimize reporting bias, are needed. Such data could be used to estimate the extent to which AI contributes to South Africa's HIV epidemic.

Transient Peripheral Immune Activation follows Elective Sigmoidoscopy or Circumcision in a Cohort Study of MSM at Risk of HIV Infection.

BACKGROUND: Rectal and genital sampling in HIV prevention trials permits assessments at the site of HIV entry. Yet the safety and acceptability of circumcision and sigmoidoscopy (and associated abstinence recommendations) are unknown in uncircumcised men who have sex with men (MSM) at high risk of HIV infection. METHODS: Twenty-nine HIV-seronegative high-risk Peruvian MSM agreed to elective sigmoidoscopy biopsy collections (weeks 2 and 27) and circumcision (week 4) in a 28-week cohort study designed to mimic an HIV vaccine study mucosal collection protocol. We monitored adherence to abstinence recommendations, procedure-related complications, HIV infections, peripheral immune activation, and retention. RESULTS: Twenty-three (79.3%) underwent a first sigmoidoscopy, 21 (72.4%) were circumcised, and 16 (55.2%) completed a second sigmoidoscopy during the study period. All who underwent procedures completed the associated follow-up safety visits. Those completing the procedures reported they were well tolerated, and complication rates were similar to those reported in the literature. Immune activation was detected during the healing period (1 week post-sigmoidoscopy, 6 weeks post-circumcision), including increases in CCR5+CD4+T cells and α4ß7+CD4+T cells. Most participants adhered to post-circumcision abstinence recommendations whereas reduced adherence occurred post-sigmoidoscopy. CONCLUSION: Rectosigmoid mucosal and genital tissue collections were safe in high-risk MSM. Although the clinical implications of the post-procedure increase in peripheral immune activation markers are unknown, they reinforce the need to provide ongoing risk reduction counseling and support for post-procedure abstinence recommendations. Future HIV vaccine studies should also consider the effects of mucosal and tissue collections on peripheral blood endpoints in trial design and analysis. TRIAL REGISTRATION: ClinicalTrials.gov NCT02630082.

Vaccination With Heterologous HIV-1 Envelope Sequences and Heterologous Adenovirus Vectors Increases T-Cell Responses to Conserved Regions: HVTN 083.

BACKGROUND: Increasing the breadth of human immunodeficiency virus type 1 (HIV-1) vaccine-elicited immune responses or targeting conserved regions may improve coverage of circulating strains. HIV Vaccine Trials Network 083 tested whether cellular immune responses with these features are induced by prime-boost strategies, using heterologous vectors, heterologous inserts, or a combination of both. METHODS: A total of 180 participants were randomly assigned to receive combinations of adenovirus vectors (Ad5 or Ad35) and HIV-1 envelope (Env) gene inserts (clade A or B) in a prime-boost regimen. RESULTS: T-cell responses to heterologous and homologous insert regimens targeted a similar number of epitopes (ratio of means, 1.0; 95% confidence interval [CI], .6-1.6; P = .91), but heterologous insert regimens induced significantly more epitopes that were shared between EnvA and EnvB than homologous insert regimens (ratio of means, 2.7; 95% CI, 1.2-5.7; P = .01). Participants in the heterologous versus homologous insert groups had T-cell responses that targeted epitopes with greater evolutionary conservation (mean entropy [±SD], 0.32 ± 0.1 bits; P = .003), and epitopes recognized by responders provided higher coverage (49%; P = .035). Heterologous vector regimens had higher numbers of total, EnvA, and EnvB epitopes than homologous vector regimens (P = .02, .044, and .045, respectively). CONCLUSIONS: These data demonstrate that vaccination with heterologous insert prime boosting increased T-cell responses to shared epitopes, while heterologous vector prime boosting increased the number of T-cell epitopes recognized. CLINICAL TRIALS REGISTRATION: NCT01095224.

Induction of HIV-1-specific mucosal immune responses following intramuscular recombinant adenovirus serotype 26 HIV-1 vaccination of humans.

BACKGROUND: Defining mucosal immune responses and inflammation to candidate human immunodeficiency virus type 1 (HIV-1) vaccines represents a current research priority for the HIV-1 vaccine field. In particular, it is unclear whether intramuscular immunization can elicit immune responses at mucosal surfaces in humans. METHODS: In this double-blind, randomized, placebo-controlled clinical trial, we evaluated systemic and mucosal immune responses to a candidate adenovirus serotype 26 (Ad26) vectored HIV-1 envelop (Env) vaccine in baseline Ad26-seronegative and Ad26-seropositive healthy volunteers. Systematic mucosal sampling with rectal Weck-Cel sponges and rectal biopsies were performed. RESULTS: Intramuscular immunization elicited both systemic and mucosal Env-specific humoral and cellular immune responses in the majority of subjects. Individuals with preexisting Ad26-specific neutralizing antibodies had vaccine-elicited immune responses comparable to those of subjects who were Ad26 seronegative. We also observed no increase in activated total or vector-specific mucosal CD4+ T lymphocytes following vaccination by either histopathology or flow cytometry. CONCLUSIONS: These data demonstrate that a single intramuscular administration of this Ad26-vectored HIV-1 Env vaccine elicited both systemic and mucosal immune responses in humans. Induction of antigen-specific humoral and cellular mucosal immunity was not accompanied by a detectable increase in mucosal inflammation. CLINICAL TRIALS REGISTRATION: NCT01103687.

First-in-human evaluation of a hexon chimeric adenovirus vector expressing HIV-1 Env (IPCAVD 002).

BACKGROUND: We report the first-in-human safety and immunogenicity assessment of a prototype hexon chimeric adenovirus (Ad) serotype 5 (Ad5) vector containing the hexon hypervariable regions of Ad serotype 48 (Ad48) and expressing human immunodeficiency virus (HIV) type 1 EnvA. METHODS: Forty-eight Ad5 and Ad48 seronegative, HIV-uninfected subjects were enrolled in a randomized, double-blind, placebo-controlled, dose escalation phase 1 study. Four groups of 12 subjects received 10(9) to 10(11) viral particles (vp) of the Ad5HVR48.EnvA.01 vaccine (n = 10 per group) or placebo (n = 2 per group) at week 0 or weeks 0, 4, and 24. Safety and immunogenicity were assessed. RESULTS: Self-limited reactogenicity was observed after the initial immunization in the highest (10(11) vp) dose group. Responses in vaccinees included Ad48 neutralizing antibody (nAb) titers higher than Ad5 nAb titers, EnvA-specific enzyme-linked immunosorbent assay titers, and EnvA-specific enzyme-linked immunospot assay responses, and these responses generally persisted at week 52. At week 28 in the 10(9), 10(10), and 10(11) vp 3-dose groups, geometric mean EnvA enzyme-linked immunosorbent assay titers were 5721, 10 929, and 3420, respectively, and Ad48 nAb titers were a median of 1.7-fold higher than for Ad5. CONCLUSIONS: Ad5HVR48.ENVA.01 was safe, well tolerated, and immunogenic at all doses tested. Vector-elicited nAb responses were greater for Ad48 than Ad5, confirming that Ad-specific nAbs in humans are primarily, but not exclusively, directed against the hexon hypervariable regions. Clinical Trials Registration. NCT00695877.

Conceptual framework for behavioral and social science in HIV vaccine clinical research.

HIV vaccine clinical research occurs within a context where biomedical science and social issues are interlinked. Previous HIV vaccine research has considered behavioral and social issues, but often treated them as independent of clinical research processes. Systematic attention to the intersection of behavioral and social issues within a defined clinical research framework is needed to address gaps, such as those related to participation in trials, completion of trials, and the overall research experience. Rigorous attention to these issues at project inception can inform trial design and conduct by matching research approaches to the context in which trials are to be conducted. Conducting behavioral and social sciences research concurrent with vaccine clinical research is important because it can help identify potential barriers to trial implementation, as well as ultimate acceptance and dissemination of trial results. We therefore propose a conceptual framework for behavioral and social science in HIV vaccine clinical research and use examples from the behavioral and social science literature to demonstrate how the model can facilitate identification of significant areas meriting additional exploration. Standardized use of the conceptual framework could improve HIV vaccine clinical research efficiency and relevance.

Behavioral and social science in HIV vaccine clinical research: Workshop report.

In May 2009, a workshop was held in Washington DC to identify ways in which HIV vaccine clinical research could benefit from and better incorporate behavioral and social science (BSS) considerations. Seventy-one people from government, non-government, and private organizations participated, including HIV vaccine researchers, clinical trial scientists, BSS researchers, community representatives, and sponsors. This workshop elucidated the opportunities and challenges for integrating BSS in HIV vaccine research by highlighting insights gained from previous BSS research on HIV prevention and highlighting new BSS approaches and methodologies. Meeting participants identified priority areas where BSS methodologies could significantly impact HIV research and developed concrete recommendations for addressing current challenges encountered in HIV vaccine research relating to social impact, risk assessment, community engagement, informed consent, risk reduction, and special populations. These recommendations address the need for improving the accuracy of participant data; standardizing data collection to enable comparisons across studies; engaging the community at all levels; using evidenced-based counseling techniques; understanding the needs and concerns of target populations; and considering the impacts of macro-level forces and influences. The importance of establishing collaborations that can carry out these recommendations and facilitate necessary changes in thinking and practice was emphasized throughout the meeting.