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The Antibody Mediated Prevention trials showed that the broadly neutralizing antibody (bnAb) VRC01 prevented acquisition of human immunodeficiency virus-1 (HIV-1) sensitive to VRC01. Using AMP trial data, here we show that the predicted serum neutralization 80% inhibitory dilution titer (PT80) biomarker—which quantifies the neutralization potency of antibodies in an individual’s serum against an HIV-1 isolate—can be used to predict HIV-1 prevention efficacy. Similar to the results of nonhuman primate studies, an average PT80 of 200 (meaning a bnAb concentration 200-fold higher than that required to reduce infection by 80% in vitro) against a population of probable exposing viruses was estimated to be required for 90% prevention efficacy against acquisition of these viruses. Based on this result, we suggest that the goal of sustained PT80 >200 against 90% of circulating viruses can be achieved by promising bnAb regimens engineered for long half-lives. We propose the PT80 biomarker as a surrogate endpoint for evaluation of bnAb regimens, and as a tool for benchmarking candidate bnAb-inducing vaccines.

Background Whether a broadly neutralizing antibody (bnAb) can be used to prevent human immunodeficiency virus type 1 (HIV-1) acquisition is unclear. Methods We enrolled at-risk cisgender men and transgender persons in the Americas and Europe in the HVTN 704/HPTN 085 trial and at-risk women in sub-Saharan Africa in the HVTN 703/HPTN 081 trial. Participants were randomly assigned to receive, every 8 weeks, infusions of a bnAb (VRC01) at a dose of either 10 or 30 mg per kilogram (low-dose group and high-dose group, respectively) or placebo, for 10 infusions in total. HIV-1 testing was performed every 4 weeks. The VRC01 80% inhibitory concentration (IC80) of acquired isolates was measured with the TZM-bl assay. Results Adverse events were similar in number and severity among the treatment groups within each trial. Among the 2699 participants in HVTN 704/HPTN 085, HIV-1 infection occurred in 32 in the low-dose group, 28 in the high-dose group, and 38 in the placebo group. Among the 1924 participants in HVTN 703/HPTN 081, infection occurred in 28 in the low-dose group, 19 in the high-dose group, and 29 in the placebo group. The incidence of HIV-1 infection per 100 person-years in HVTN 704/HPTN 085 was 2.35 in the pooled VRC01 groups and 2.98 in the placebo group (estimated prevention efficacy, 26.6%; 95% confidence interval [CI], -11.7 to 51.8; P = 0.15), and the incidence per 100 person-years in HVTN 703/HPTN 081 was 2.49 in the pooled VRC01 groups and 3.10 in the placebo group (estimated prevention efficacy, 8.8%; 95% CI, -45.1 to 42.6; P = 0.70). In prespecified analyses pooling data across the trials, the incidence of infection with VRC01-sensitive isolates (IC80 Conclusions VRC01 did not prevent overall HIV-1 acquisition more effectively than placebo, but analyses of VRC01-sensitive HIV-1 isolates provided proof-of-concept that bnAb prophylaxis can be effective. (Supported by the National Institute of Allergy and Infectious Diseases; HVTN 704/HPTN 085 and HVTN 703/HPTN 081 ClinicalTrials.gov numbers, NCT02716675 and NCT02568215.).

Background HIV Vaccine Trials Network 703/HIV Prevention Trials Network 081 is a phase 2b randomized, double-blind, placebo-controlled trial to assess the safety and efficacy of passively infused monoclonal antibody VRC01 in preventing HIV acquisition in heterosexual women between the ages of 18 and 50 years at risk of HIV. Participants were enrolled at 20 sites in Botswana, Kenya, Malawi, Mozambique, South Africa, Tanzania, and Zimbabwe. It is one of the 2 Antibody Mediated Prevention efficacy trials, with HIV Vaccine Trials Network 704/HIV Prevention Trials Network 085, evaluating VRC01 for HIV prevention. Methods Intense community engagement was used to optimize participant recruitment and retention. Participants were randomly assigned to receive intravenous VRC01 10 mg/kg, VRC01 30 mg/kg, or placebo in a 1:1:1 ratio. Infusions were given every 8 weeks with a total of 10 infusions and 104 weeks of follow-up after the first infusion. Results Between May 2016 and September 2018, 1924 women from sub-Saharan Africa were enrolled. The median age was 26 years (interquartile range: 22-30), and 98.9% were Black. Sexually transmitted infection prevalence at enrollment included chlamydia (16.9%), trichomonas (7.2%), gonorrhea (5.7%), and syphilis (2.2%). External condoms (83.2%) and injectable contraceptives (61.1%) were the methods of contraception most frequently used by participants. In total, through April 3, 2020, 38,490 clinic visits were completed with a retention rate of 96% and 16,807 infusions administered with an adherence rate of 98%. Conclusions This proof-of-concept, large-scale monoclonal antibody study demonstrates the feasibility of conducting complex trials involving intravenous infusions in high incidence populations in sub-Saharan Africa.

BACKGROUND The Antibody-Mediated Prevention trials (HVTN 704/HPTN 085 and HVTN 703/HPTN 081) are the first efficacy trials to evaluate whether VRC01, a broadly neutralizing monoclonal antibody targeting the CD4-binding site of the HIV envelope protein, prevents sexual transmission of HIV-1. HVTN 704/HPTN 085 enrolled 2701 cisgender men and transgender (TG) individuals who have sex with men at 26 sites in Brazil, Peru, Switzerland, and the United States. METHODS Participants were recruited and retained through early, extensive community engagement. Eligible participants were randomized 1:1:1 to 10 mg/kg or 30 mg/kg of VRC01 or saline placebo. Visits occurred monthly, with intravenous (IV) infusions every 8 weeks over 2 years, for a total of 10 infusions. Participants were followed for 104 weeks after first infusion. RESULTS The median HVTN 704/HPTN 085 participant age was 28 years; 99% were assigned male sex; 90% identified as cisgender men, 5% as TG women and the remaining as other genders. Thirty-two percent were White, 15% Black, and 57% Hispanic/Latinx. Twenty-eight percent had a sexually transmitted infection at enrollment. More than 23,000 infusions were administered with no serious IV administration complications. Overall, retention and adherence to the study schedule exceeded 90%, and the dropout rate was below 10% annually (7.3 per 100 person-years) through week 80, the last visit for the primary end point. CONCLUSIONS HVTN 704/HPTN 085 exceeded accrual and retention expectations. With exceptional safety of IV administration and operational feasibility, it paves the way for future large-scale monoclonal antibody trials for HIV prevention and/or treatment.

Background The Antibody-mediated Prevention (AMP) trials (HVTN 704/HPTN 085 and HVTN 703/HPTN 081) are the first efficacy trials to evaluate whether VRC01, a broadly neutralizing antibody (bnAb) that targets CD4 binding site of HIV envelope, prevents HIV acquisition in uninfected individuals. In these ongoing trials, 10 intravenous (IV) infusions of VRC01 are given every 8 weeks over a period of 2 years. We report on interim operational feasibility, enrollment and safety. Methods Participant recruitment was enhanced by extensive community engagement and education. Eligible participants were randomly assigned 1:1:1 to 10mg/kg, 30mg/kg of VRC01 or saline placebo. HVTN 704/HPTN 085 enrolled high-risk men (MSM) and transgender (TG) individuals who have sex with men at 26 sites in United States, Peru, Brazil, and Switzerland. HVTN 703/HPTN 081 enrolled high-risk heterosexual women at 20 sites in Botswana, Kenya, Malawi, Mozambique, South Africa, Tanzania, and Zimbabwe. HIV testing occurs monthly. Results In October 2018, the AMP trials completed enrollment of 4,625 participants. Enrollment met or exceeded targets throughout the trial period, peaked at 298 participants/month, and was slowed mid-trial to allow for sufficient drug supply at trial sites. In HVTN 704/HPTN 085, 2701 (target N = 2700) MSM/TG participants 18–50yrs were enrolled with median age of 28; 99% born male; 90% identified as male gender and 5% TG female. Race/ethnicity was 32% White, 15% Black and 57% Hispanic/Latino/a. 28% had a sexually transmitted infection (STI) including gonorrhea (GC), chlamydia (CT) or syphilis at enrollment. In HVTN 703/HPTN 081,1924 (target N = 1900) women 18–40yrs were enrolled with median age of 26;100% were born female (53% female gender, 47% gender not assessed); 99% were Black. 26% had a STI at enrollment including GC, CT, trichomonas or syphilis. Overall 36,945 infusions have been given so far with no serious procedural complications due to IV administration. Retention and adherence to the rigorous study schedule (monthly visits for 2 years) remain within an acceptable range. Conclusion The AMP trials have exceeded enrollment of target populations and are maintaining high rates of retention. With exceptional safety and operational feasibility, they are paving the way for future large-scale bnAb trials for HIV prevention and/or treatment. Disclosures All authors: No reported disclosures.

The HIV Vaccine Trials Network (HVTN) 087 vaccine trial assessed the effect of increasing doses of pIL-12 (interleukin-12 delivered as plasmid DNA) adjuvant on the immunogenicity of an HIV-1 multiantigen (MAG) DNA vaccine delivered by electroporation and boosted with a vaccine comprising an attenuated vesicular stomatitis virus expressing HIV-1 Gag (VSV-Gag). We randomized 100 healthy adults to receive placebo or 3 mg HIV-MAG DNA vaccine (ProfectusVax HIV-1 gag / pol or ProfectusVax nef / tat / vif , env ) coadministered with pIL-12 at 0, 250, 1,000, or 1,500 μg intramuscularly by electroporation at 0, 1, and 3 months followed by intramuscular inoculation with 3.4 × 10 7 PFU VSV-Gag vaccine at 6 months. Immune responses were assessed after the prime and boost and 6 months after the last vaccination. High-dose pIL-12 increased the magnitude of CD8 + T-cell responses postboost compared to no pIL-12 ( P = 0.02), while CD4 + T-cell responses after the prime were higher in the absence of pIL-12 than with low- and medium-dose pIL-12 ( P ≤ 0.05). The VSV boost increased Gag-specific CD4 + and CD8 + T-cell responses in all groups ( P < 0.001 for CD4 + T cells), inducing a median of four Gag epitopes in responders. Six to 9 months after the boost, responses decreased in magnitude, but CD8 + T-cell response rates were maintained. The addition of a DNA prime dramatically improved responses to the VSV vaccine tested previously in the HVTN 090 trial, leading to broad epitope targeting and maintained CD8 + T-cell response rates at early memory. The addition of high-dose pIL-12 given with a DNA prime by electroporation and boosted with VSV-Gag increased the CD8 + T-cell responses but decreased the CD4 + responses. This approach may be advantageous in reshaping the T-cell responses to a variety of chronic infections or tumors. (This study has been registered at ClinicalTrials.gov under registration no. NCT01578889.)

BackgroundAnti-HIV-1 broadly neutralizing antibodies (bnAbs) have been developed as potential agents for prevention of HIV-1 infection. The HIV Vaccine Trials Network and the HIV Prevention Trials Network are conducting the Antibody Mediated Prevention (AMP) trials to assess whether, and how, intravenous infusion of the anti-CD4 binding site bnAb, VRC01, prevents HIV-1 infection. These are the first test-of-concept studies to assess HIV-1 bnAb prevention efficacy in humans.MethodsThe AMP trials are two parallel phase 2b HIV-1 prevention efficacy trials conducted in two cohorts: 2700 HIV-uninfected men and transgender persons who have sex with men in the United States, Peru, Brazil, and Switzerland; and 1500 HIV-uninfected sexually active women in seven countries in sub-Saharan Africa. Participants are randomized 1:1:1 to receive an intravenous infusion of 10 mg/kg VRC01, 30 mg/kg VRC01, or a control preparation every 8 weeks for a total of 10 infusions. Each trial is designed (1) to assess overall prevention efficacy (PE) pooled over the two VRC01 dose groups vs. control and (2) to assess VRC01 dose and laboratory markers as correlates of protection (CoPs) against overall and genotype- and phenotype-specific infection.ResultsEach AMP trial is designed to have 90 % power to detect PE > 0 % if PE is ≥ 60 %. The AMP trials are also designed to identify VRC01 properties (i. e., concentration and effector functions) that correlate with protection and to provide insight into mechanistic CoPs. CoPs are assessed using data from breakthrough HIV-1 infections, including genetic sequences and sensitivities to VRC01-mediated neutralization and Fc effector functions.ConclusionsThe AMP trials test whether VRC01 can prevent HIV-1 infection in two study populations. If affirmative, they will provide information for estimating the optimal dosage of VRC01 (or subsequent derivatives) and identify threshold levels of neutralization and Fc effector functions associated with high-level protection, setting a benchmark for future vaccine evaluation and constituting a bridge to other bnAb approaches for HIV-1 prevention.

Attenuated, replication-competent viral vector vaccines are highly immunogenic in that they mimic natural infection. They offer the promise of eliciting a more integrated immune response and more abundant and sustained expression of the encoded viral antigens. Although a vaccine to prevent human immunodeficiency virus (HIV) infection remains an urgent global health priority, concerns about the safety of using live-attenuated HIV itself as a vaccine [1] has led the field to focus heavily on the exploration of replication-defective viral vectors to deliver HIV-1 antigens. There are limited data to suggest these vectors are able to induce an optimal, integrated immune response, which may include CD4+ T-cell help for B-cell/antibody and polyfunctional cytotoxic T-cell responses together with long-term immunologic memory [2]. To date, only 1 replication-defective viral vector, based on canarypox, administered sequentially with a gp120 subunit boost vaccine, has demonstrated partial protection from HIV acquisition in an efficacy trial [3]. Currently, only a few replicating viruses, including vaccinia (clinical trial ID NCT01705223), Sendai virus (NCT01705990), measles (NCT01320176), and adenovirus subtype 4 (NCT01989533), have advanced to clinical trials as HIV-1 vaccine vectors. Vesicular stomatitis virus (VSV) is a member of the genus Vesiculovirus in the family Rhabdoviridae. The 2 major serotypes are New Jersey and Indiana. Vesicular stomatitis virus has a single-strand, negative-sense, nonsegmented RNA genome. Similar to Sendai and measles viruses, the virus genomic organization of VSV (Figure ​(Figure1A)1A) and life cycle make it particularly attractive as a candidate vaccine vector because the genome can accommodate multiple gene inserts, is stable over many generations, and does not undergo recombination. In addition, the VSV genome replicates in the cytoplasm and is incapable of integrating within the genomes of infected host cells. Finally, VSV is a zoonosis, cycling between biting insects and livestock (cattle, horses, and swine). Human infection with VSV is rare in most regions of the world except in certain regions of Central and South America where VSV is endemic. Where VSV infection does occur, it is typically asymptomatic or is associated with an acute influenza-like illness with symptoms such as fever, muscle aches, and malaise [4, 5]. Thus, the general population is largely free of pre-existing, virus-neutralizing immunity—a factor that has limited the clinical utility of HIV-1 vaccines based on adenovirus subtype 5 [6, 7]. Figure 1. (A) Wild-type vesicular stomatitis virus (VSV) genome organization and virion structure. Viral transcription is polar, initiating at the single 3′ promoter and proceeding to the 5′ end of the genome, producing a steep 3′ to 5′ ... Recombinant VSV (rVSV) has been extensively studied as a potential HIV vaccine vector in preclinical, nonhuman primate (NHP) models [8–11]. After 2 sequential immunizations, rhesus macaques that received rVSV expressing HIV-1 env and simian immunodeficiency virus (SIV) gag were all infected but were protected from disease progression for 4 years or more after infection with SHIV 89.6P, maintaining low or undetectable viral load set points and preserved CD4+ T-cell counts [11]. This encouraging level of postchallenge protection from disease suggested that rVSV vectors expressing HIV genes might be an effective HIV vaccine in humans. To maximize safety for first-in-human clinical evaluation, a highly attenuated form of rVSV Indiana was developed. This involved downregulating VSV N protein expression by translocating the N gene further away from the 3′ transcription promoter and truncating the VSV G protein cytoplasmic tail from 29 amino acids found in wild-type virus to a single amino acid [12]. In addition, HIV-1 gag expression was achieved by insertion of the gag gene adjacent to the 3′ transcription promoter (Figure ​(Figure1B).1B). The resulting vector (rVSVN4CT1gag1) was shown to be safe, well tolerated, and immunogenic in several murine and NHP studies [13, 14]. In the work described here, the HIV Vaccine Trials Network (HVTN) evaluated the safety and immunogenicity of this novel vaccine vector in a phase 1a dose-escalation, first-in-human trial, HVTN 090.

BACKGROUND. Vector prime-boost immunization strategies induce strong cellular and humoral immune responses. We examined the priming dose and administration order of heterologous vectors in HIV Vaccine Trials Network 078 (HVTN 078), a randomized, double-blind phase Ib clinical trial to evaluate the safety and immunogenicity of heterologous prime-boost regimens, with a New York vaccinia HIV clade B (NYVAC-B) vaccine and a recombinant adenovirus 5–vectored (rAd5-vectored) vaccine. METHODS. NYVAC-B included HIV-1 clade B Gag-Pol-Nef and gp120, while rAd5 included HIV-1 clade B Gag-Pol and clades A, B, and C gp140. Eighty Ad5-seronegative subjects were randomized to receive 2 × NYVAC-B followed by 1 × 1010 PFU rAd5 (NYVAC/Ad5hi); 1 × 108 PFU rAd5 followed by 2 × NYVAC-B (Ad5lo/NYVAC); 1 × 109 PFU rAd5 followed by 2 × NYVAC-B (Ad5med/NYVAC); 1 × 1010 PFU rAd5 followed by 2 × NYVAC-B (Ad5hi/NYVAC); or placebo. Immune responses were assessed 2 weeks after the final vaccination. Intracellular cytokine staining measured T cells producing IFN-γ and/or IL-2; cross-clade and epitope-specific binding antibodies were determined; and neutralizing antibodies (nAbs) were assessed with 6 tier 1 viruses. RESULTS. CD4+ T cell response rates ranged from 42.9% to 93.3%. NYVAC/Ad5hi response rates (P ≤ 0.01) and magnitudes (P ≤ 0.03) were significantly lower than those of other groups. CD8+ T cell response rates ranged from 65.5% to 85.7%. NYVAC/Ad5hi magnitudes were significantly lower than those of other groups (P ≤ 0.04). IgG response rates to the group M consensus gp140 were 89.7% for NYVAC/Ad5hi and 21.4%, 84.6%, and 100% for Ad5lo/NYVAC, Ad5med/NYVAC, and Ad5hi/NYVAC, respectively, and were similar for other vaccine proteins. Overall nAb responses were low, but aggregate responses appeared stronger for Ad5med/NYVAC and Ad5hi/NYVAC than for NYVAC/Ad5hi. CONCLUSIONS. rAd5 prime followed by NYVAC boost is superior to the reverse regimen for both vaccine-induced cellular and humoral immune responses. Higher Ad5 priming doses significantly increased binding and nAbs. These data provide a basis for optimizing the design of future clinical trials testing vector-based heterologous prime-boost strategies. TRIAL REGISTRATION. ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00961883","term_id":"NCT00961883"}}NCT00961883. FUNDING. NIAID, NIH UM1AI068618, {"type":"entrez-nucleotide","attrs":{"text":"AI068635","term_id":"3391610","term_text":"AI068635"}}AI068635, {"type":"entrez-nucleotide","attrs":{"text":"AI068614","term_id":"3391589","term_text":"AI068614"}}AI068614, and {"type":"entrez-nucleotide","attrs":{"text":"AI069443","term_id":"3392418","term_text":"AI069443"}}AI069443.

Results For CD4+ T cells, the overall response rates for IFN-g and/or IL-2 among the vaccinees were 42.9%, 93.3%, 92.3%, and 85.7% for T1-T4, respectively; and the median response magnitudes for positive responders were 0.26%, 0.76%, 0.40%, and 0.76% for T1- T4, respectively. Both response rates (p

The development of a safe and effective vaccine against human immunodeficiency virus type 1 (HIV-1) is a major goal of biomedical research and public health efforts [1–5]. The precise immune responses that might provide protection against HIV infection remain undefined, and multiple approaches to vaccination against HIV-1 have therefore been studied [6–8]. Evidence suggests that virus-specific cytotoxic T lymphocyte CD8+ responses are particularly important for control of HIV-1 replication in humans [9, 10] and simian immunodeficiency virus (SIV) infection in nonhuman primates [11–13]. In addition, virus-specific CD4+ T cell responses have also been associated with control of HIV-1 viremia [14]. One approach to developing a vaccine against HIV-1 has been to use plasmid DNA that encodes HIV antigens and stimulates T-cell and antibody responses in mice and nonhuman primates and humans [3, 15–19]. This approach has been safe and partially efficacious, and coadministration of plasmid-encoded immunomodulator molecules has been used to improve DNA vaccine–elicited HIV-specific cellular immune responses in mice [20]. Interleukin (IL) 2 has been evaluated as a potential adjuvant to augment immune responses in HIV infection and as a potential antitumor agent. Given its short half-life, large systemic doses of IL-2 have been used in clinical studies [21–23]. However, the in vitro half-life of IL-2 can be prolonged by fusion of IL-2 with the Fc protein of immunoglobulin G (IgG) 2 and still retain IL-2 activity. The IL-2–immunoglobulin (IL-2/Ig) fusion protein has been shown to be significantly more effective than IL-2 alone in augmenting immune responses to HIV-1 gp120 plasmid DNA in mice [24]. Augmented immune responses have also been observed with use of a plasmid DNA coding IL-2/Ig. However, these data suggested that the timing of cytokine administration may be an important variable, because the highest immune responses were seen when plasmid IL-2/Ig was administered 2 days after the HIV-1 gp120 plasmid DNA vaccine, rather than concurrently with the vaccine. A subsequent study in rhesus monkeys showed that administration of plasmid IL-2/Ig was more effective than administration of IL-2/Ig protein in augmentation of immune responses to SIV DNA vaccine [25]. Vaccination of rhesus monkeys with DNA vaccines expressing SIVmac239 gag and SHIV-89.6P env, along with either plasmid IL-2/Ig (given 48 hours after DNA vaccination) or IL-2/Ig protein, and subsequently challenge with SHIV-89.6P, resulted in a low to undetectable viral load set point and lack of clinical disease [13]. These findings provided the rationale and guidance for the experimental design of the clinical trial that we conducted. The clinical study was designed as a randomized, double-blind, placebo-controlled dose escalation phase I trial to determine the safety, tolerability, and immunogenicity of an HIV-1 DNA vaccine [3] administered with plasmid IL-2/Ig to HIV-1–uninfected healthy adults. The regimen of the maximum tolerated dose of plasmid IL-2/Ig administered simultaneously with the plasmid HIV-1 vaccine, was then compared with the regimen of IL-2/Ig administered 48 hours after the HIV-1 DNA vaccine.

Differences in morningness-eveningness among humans are commonly ascribed to circadian parameters, such as circadian period and responsivity to environmental time cues, as well as homeostatic sleep drive. Light is the primary synchronizer of the human biological clock, and if circadian differences exist between morning and evening types, they should have different phase angles of entrainment to the light/dark cycle; that is, morning and evening types should have different patterns of light exposure relative to endogenous circadian phase (ECP). When phase angle of entrainment is strictly defined as the relationship between a marker of ECP and the timing of light exposure, such differences have been demonstrated in the laboratory under controlled light/dark cycles and have recently been shown under conditions of spring and summer light exposure outside the laboratory, taking into account the variable intensity of light. Here, we report similar results from a large (n = 66), diverse cohort of morning and evening types across the age span studied at all different times of the year. Differences between morning and evening types in light exposure relative to ECP, indicative of a difference in the phase angle of entrainment to the external light/dark cycle, were found. Specifically, evening types, compared to morning types, had a higher ratio of phase advancing to phase delaying by light. We interpret this as indicating a longer circadian period (τ) in evening types.

This paper reviews the statistical analyses of competing risks data. There is an extensive history of this topic; however, the literature is often confusing partially because it evolved over time. The available data for competing risks is in the form of time until event occurrence where T is the time from some suitable starting point until some cause of failure for each individual who fails, and δi is an indicator variable equal to 1 if failure is due to the ith cause, 0 otherwise. In the latent failure time approach, one assumes that there are k potential failure times, X1, X2, …, Xk, associated with each risk. T is then the min (X1, X2, …, Xk) and δi is an indicator variable equal to 1 if failure is due to the ith cause, 0 otherwise. References for the latent failure time model prior to the 1970s may be found in David and Moeschberger (1978), and more recently in Klein and Moeschberger (2003). The direction of the statistical analyses of competing risks studies changed dramatically after the identifiability problem for marginal distributions of the latent failure time model was pointed out by Tsiatis (1975), Prentice et al. (1978), and many others. At that time, interest centered on estimating identifiable competing risk probabilities. Most of the references cited in this paper deal with the more recent attempts to analyze competing risks data.

High frequency responses were elicited against clade A (T1 95.8%, T2 100%, T3 97.4%, T4 100%), clade B (T1 95.8%, T2 95.0%, T3 92.1%, T4 96.3%), clade C (T1 92%, T2 76%, T3 76%, T4 78%), and Con S (T1-4 100%). There were no significant between-group differences in response frequency or magnitude. The majority also had responses to V1V2 clade A (T1 100%, T2 87.8%, T3 83.8%, T4 85.2%) and clade B (T1 58.3%, T2 65.9%, T3 54.1%, T4 51.9%). The mean fluorescent intensity was higher in T2 vs T1 (p=0.005) for clade A V1V2. No significant differences were observed between other groups.

Methods HVTN 090 enrolled sixty healthy, HIV-1-uninfected adults in a randomized, double-blinded, placebo-controlled dose escalation study. Groups of 12 participants received rVSV Indiana HIV Gag vaccine at 5 dose levels (4.6 x 10 to 3.4 x 10 PFU) (N=10/group) or placebo (N=2/group), delivered intramuscularly at 0 and 2 months. Reactogenicity over 7 days, adverse events (AEs), and viral cultures from whole blood, urine, saliva and swabs of oral lesions were collected. HIV-1-specific CD4+ and CD8+ T-cell responses to Gag peptides were measured 1 and 2 weeks post-boost by intracellular cytokine staining.