HIV vaccine development
HIV vaccine development comprises the scientific and clinical pursuits to engineer a preventive vaccine against human immunodeficiency virus type 1 (HIV-1), the primary causative agent of acquired immunodeficiency syndrome (AIDS). Launched in the early 1980s following HIV-1's isolation, these endeavors have tested myriad immunogen designs—including recombinant proteins, viral vectors, and nucleic acid-based platforms—across more than 300 trials, encompassing 11 pivotal efficacy studies, yet have failed to deliver a licensed vaccine capable of reliably blocking infection.[1][2] Key hurdles stem from HIV-1's extraordinary antigenic variability, driven by error-prone reverse transcriptase and high replication rates, which generate diverse quasispecies evading conventional antibody and T-cell responses, alongside the virus's capacity to deplete CD4+ T cells essential for adaptive immunity.[3][4] The sole modestly efficacious trial, RV144 in Thailand (2009), achieved approximately 31% protection via a canarypox prime and gp120 boost regimen, attributed partly to non-neutralizing antibodies, but follow-up efforts like VAX003 and recent vector-based trials yielded null or negligible results.[1][5] Promising leads, such as broadly neutralizing antibodies (bNAbs) targeting conserved envelope epitopes and germline-targeting immunogens to initiate bNAb lineages, persist in preclinical and early-phase testing, including mRNA platforms, though phase 3 validations like the 2024 PrEPVacc study confirmed ineffectiveness of tested regimens, highlighting ongoing empirical setbacks and the imperative for novel correlates of protection beyond empirical trial-and-error.[2][6][7] Despite four decades of investment yielding insights into HIV immunobiology, the field's stagnation—evident in recent funding reallocations away from certain consortia—underscores causal complexities in inducing sterilizing immunity absent from natural controllers, fueling scrutiny of traditional vaccine paradigms.[8][9]Historical Background
Early Research and Initial Efforts (1980s–1990s)
The identification of HIV as the causative agent of AIDS in 1983 by French researchers at the Pasteur Institute, led by Luc Montagnier, and independently in 1984 by Robert Gallo's team at the U.S. National Cancer Institute, spurred immediate vaccine research initiatives.[10] Early efforts emphasized the virus's envelope glycoproteins, particularly gp120 and gp160, as targets for neutralizing antibodies, drawing from successes with other viral vaccines like hepatitis B.[10] In April 1984, U.S. Secretary of Health and Human Services Margaret Heckler publicly stated that an effective AIDS vaccine would be ready for human testing within two years, reflecting initial optimism amid the escalating epidemic but underestimating HIV's mutational rate and integration into host DNA.[10] Preclinical studies in the mid-1980s utilized chimpanzees, the only non-human primate susceptible to HIV infection, to test recombinant subunit vaccines. These models demonstrated transient protection against low-dose viral challenges with envelope-based immunogens, but inconsistent results underscored the limitations of extrapolating to humans due to HIV's adaptation to primate hosts.[10] Vaccine candidates were produced via recombinant DNA technology in yeast or mammalian cells to avoid risks of live-virus approaches, given HIV's potential for oncogenicity and persistence.[1] By 1986, informal collaborations, including one organized by Gallo, coordinated global efforts, though challenges like the virus's rapid evolution—exhibiting up to 10% genetic divergence within individuals—were already evident from sequencing data.[11] The first human clinical trial, a Phase I safety and immunogenicity study, began in August 1987 at the NIH Clinical Center in Bethesda, Maryland, involving HIV-uninfected volunteers immunized with a recombinant gp120 envelope protein vaccine.[10] This trial, sponsored by the U.S. Army and MicroGenesys, confirmed tolerability but induced only weak, narrow neutralizing responses.[10] Through the 1990s, additional Phase I and II trials expanded to candidates like gp160 from Oncogen (Bristol-Myers Squibb) and whole-killed virus preparations, testing adjuvants such as alum or incomplete Freund's to boost immunity; however, immunogenicity remained modest and strain-specific, with no evidence of protective efficacy.[12] By 1997, over a dozen envelope-focused regimens had entered early human testing, primarily in the U.S. and Europe, but preclinical data increasingly revealed HIV's shielding of conserved epitopes, foreshadowing broader setbacks.[13] These efforts, largely driven by pharmaceutical firms like Merck and Genentech due to limited initial public funding, established safety profiles but highlighted the need for strategies beyond antibody induction.[13]Key Milestones in Pre-Clinical and Early Clinical Work
Following the identification of HIV as the causative agent of AIDS in 1984, pre-clinical vaccine research rapidly shifted to animal models, particularly simian immunodeficiency virus (SIV) in macaques and HIV-1 challenges in chimpanzees, to evaluate candidate immunogens for safety and preliminary efficacy.[10] In 1989, two independent studies reported protection in rhesus macaques: one using formalin-inactivated SIV combined with Freund's adjuvant, which prevented infection upon homologous challenge in four of four animals, and another employing a live-attenuated SIV variant (SIVmac239Δnef), which conferred sterilizing immunity against pathogenic challenge. [14] These results highlighted the potential of both inactivated and attenuated approaches but raised concerns over safety for human use, as attenuated strains carried risks of reversion to virulence.[15] By 1990, pre-clinical work advanced with recombinant envelope glycoprotein gp120, which, when administered to chimpanzees, elicited neutralizing antibodies and protected against low-dose HIV-1 challenge in two of three animals, demonstrating feasibility for subunit vaccines targeting the viral envelope. In 1992, further macaque studies confirmed durable protection from live-attenuated SIV, with vaccinated animals controlling viremia post-challenge for over a year, though incomplete sterilizing immunity underscored limitations in mimicking human transmission dynamics. These models established correlates like CD8+ T-cell responses and antibody-mediated clearance but revealed challenges in translating to heterologous HIV strains due to viral diversity.[12] Early clinical trials commenced amid optimism but prioritized safety given HIV's integration into host DNA and lack of natural immunity models. In 1986, French researcher Daniel Zagury conducted the first human trial without regulatory approval, vaccinating himself and six HIV-negative Zairian volunteers with a recombinant vaccinia vector expressing HIV-1 gp160 and other proteins; transient immune responses were observed, but ethical lapses and lack of controls limited interpretability.[11] The inaugural regulated Phase 1 trial launched in 1987 at the NIH Clinical Center, testing MicroGeneSys's recombinant gp160 subunit vaccine in 81 healthy, HIV-uninfected volunteers; it proved safe with no serious adverse events, inducing modest antibody titers but negligible cellular immunity or neutralization of primary isolates.[10] The NIAID's AIDS Vaccine Evaluation Group (AVEG) initiated its first trial in 1988, evaluating gp120 and gp160 candidates in low-risk volunteers, confirming tolerability while highlighting weak immunogenicity against diverse clades.[10] By 1992, AVEG's inaugural Phase 2 trial targeted high-risk HIV-negative individuals, incorporating risk-reduction counseling alongside vaccines like MN-rgp120; safety was affirmed, but antibody responses waned rapidly, yielding no evidence of protection in small cohorts.[10] Mid-1990s Phase 1/2 studies explored prime-boost regimens, such as canarypox vectors (ALVAC) expressing HIV antigens followed by gp120 boosts, generating CD4+ and CD8+ T-cell responses in volunteers but failing to elicit broadly neutralizing antibodies against tier-2 viruses. These trials collectively established that early envelope-based candidates induced narrow, strain-specific immunity insufficient for broad efficacy, prompting shifts toward T-cell-focused designs while exposing gaps in correlates of protection.[12]Biological and Immunological Challenges
HIV's Evasion Mechanisms and Genetic Variability
HIV-1's reverse transcriptase enzyme operates without proofreading capability, yielding a mutation rate of approximately 3 × 10^{-5} substitutions per nucleotide per replication cycle, which is substantially higher than that observed in most other viruses.[16] This elevated error rate, compounded by frequent recombination events during co-infection with multiple viral strains, generates extensive genetic diversity within a single host.[17] Consequently, HIV-1 populations form dynamic quasispecies—clouds of closely related variants differing by multiple mutations—allowing the virus to maintain a reservoir of potential escape forms that can be selected under immune pressure.[18] The envelope glycoprotein (Env), particularly the gp120 subunit, exemplifies this variability, with hypervariable regions (V1–V5 loops) exhibiting mutation rates up to 1–2% per year in chronic infection, far exceeding conserved genomic regions.[19] These mutations drive antigenic drift, enabling the virus to evade neutralizing antibodies by altering key epitopes or by accumulating N-linked glycans that shield vulnerable sites on the Env trimer.[17] For cellular immunity, genetic changes in epitopes presented by MHC class I molecules allow escape from cytotoxic T lymphocytes (CTLs), as variant peptides fail to bind HLA alleles or trigger recognition by existing T-cell receptors.[20] Such adaptations occur rapidly, often within weeks of initial immune targeting, perpetuating chronic infection.[21] Beyond raw variability, HIV-1 leverages mutations in accessory genes to counteract intrinsic host defenses, enhancing overall evasion. For instance, polymorphisms in vif inhibit APOBEC3G-mediated hypermutation, while nef variants downregulate MHC-I expression on infected cells, reducing CTL visibility without triggering compensatory NK cell activation.[22] Similarly, vpu mutations counteract tetherin to facilitate virion release.[22] This genetic plasticity positions HIV-1 near its error threshold, balancing diversity generation with functional integrity to sustain replication amid host pressures.[18] The resultant intra- and inter-clade diversity—spanning over 30% nucleotide divergence in env across global subtypes—poses profound barriers to vaccine-induced immunity capable of broad coverage.[23]Limitations of Animal Models and Correlates of Protection
Animal models for HIV vaccine development face significant limitations due to the virus's human-specific tropism and the inability of most species to naturally replicate HIV-1 infection and pathogenesis. Chimpanzees, the only non-human primate susceptible to HIV-1, rarely progress to AIDS-like disease, limiting their utility for studying chronic infection and vaccine efficacy; ethical concerns have further restricted their use since the early 2000s.[24] [25] Macaque models employing simian immunodeficiency virus (SIV) or chimeric SHIV viruses better mimic AIDS progression but diverge in immune responses, mucosal transmission routes, and viral genetics from human HIV-1, leading to poor translational predictive value.[26] [25] Humanized mouse models, such as BLT or hu-HSC mice engrafted with human hematopoietic cells, enable HIV-1 replication but suffer from incomplete immune reconstitution, lack of lymphoid architecture, and variable engraftment efficiency, precluding reliable assessment of vaccine-induced protection against systemic or mucosal challenges.[27] These models often overestimate or underestimate immunogenicity due to absent human-specific factors like mucosal immunity and T-cell trafficking, contributing to discrepancies between preclinical success and clinical failures, as seen in the STEP trial where an adenovirus-5 vectored vaccine protected macaques but increased HIV acquisition risk in humans.[26] [28] The identification of correlates of protection (CoP)—immune parameters predictive of vaccine efficacy—remains elusive for HIV-1, complicating preclinical evaluation in animal models. Unlike vaccines for pathogens with sterilizing immunity (e.g., neutralizing antibodies for hepatitis B), HIV lacks defined natural protective immunity, with no single marker like CD4 T-cell counts or broadly neutralizing antibodies (bnAbs) consistently correlating with prevention of infection across trials.[29] [30] In the RV144 trial, the only partially efficacious HIV vaccine (31% efficacy in 2009), modest CoP included low Env-specific IgA and high ADCC-mediating IgG3 antibodies, but these have not replicated in subsequent studies, highlighting context-dependency and the challenge of inducing durable, multi-epitope responses against HIV's hypervariability.[30] Animal models exacerbate this by failing to capture human-specific CoP, such as bnAb maturation requiring prolonged antigen exposure absent in short-term challenges, resulting in vaccines that elicit promising responses in non-human primates but fail to protect humans.[23] [31] Overall, these limitations underscore the need for human-centric approaches, as animal-derived CoP have historically misled development efforts despite decades of investment.[28]Vaccine Design Strategies
Traditional Approaches (e.g., Whole-Virus, Subunit Vaccines)
Subunit vaccines targeting HIV envelope glycoproteins, such as recombinant gp120 or gp160, formed the cornerstone of early traditional efforts, inspired by the success of protein-based vaccines like hepatitis B. These candidates aimed to elicit neutralizing antibodies against the viral spike protein, but clinical outcomes revealed limitations in addressing HIV's conformational epitopes and sequence diversity. The first phase I trial of a gp160 subunit vaccine occurred in 1987, yet subsequent evaluations showed no significant efficacy in preventing infection.[32] The AIDSVAX vaccine, a monomeric gp120 protein formulation developed by VaxGen, advanced to phase III testing in two trials: Vax003 (conducted 2000–2003 in Thailand with over 16,000 participants at risk) and Vax004 (1998–2002 in North America and Europe with about 5,400 participants). Both trials failed to demonstrate protective efficacy, with infection rates similar between vaccinated and placebo groups—yielding adjusted efficacy estimates of -3% to 0% after unblinding and intent-to-treat analysis. Post-trial analyses attributed the lack of success to the vaccine's induction of non-neutralizing antibodies focused on variable loops, which failed to block diverse HIV strains or mucosal transmission.[1][33] Whole-virus approaches, including inactivated preparations, were pursued cautiously due to HIV's integration into host genomes and potential for incomplete inactivation leading to latent reservoirs or oncogenicity. Unlike successful inactivated vaccines for pathogens like rabies, HIV's enveloped structure complicates antigen preservation during beta-propiolactone or formalin treatment, often resulting in diminished immunogenicity. A phase I trial of a genetically modified, inactivated whole-HIV-1 vaccine began in 2016, confirming safety in low doses but eliciting only modest antibody responses insufficient for broad protection; further advancement stalled amid concerns over scalability and regulatory hurdles for handling replication-competent residuals. Live-attenuated whole-virus strategies, effective in SIV-macaque models via nef deletion, were deemed too risky for humans given documented cases of disease progression in exposed infants.[34][35][36] These traditional methods underscored HIV's resistance to antibody-centric responses alone, as subunit vaccines generated high-titer binding antibodies without the breadth needed against glycan-shielded conserved sites, while whole-virus formats struggled with safety-immunogenicity trade-offs. By the early 2000s, failures prompted shifts toward combination regimens incorporating T-cell priming, though pure traditional designs yielded no licensed products.[3][23]Novel Approaches Targeting Broadly Neutralizing Antibodies (bnAbs)
Broadly neutralizing antibodies (bnAbs) target conserved epitopes on the HIV-1 envelope glycoprotein (Env), offering potential for vaccines that neutralize diverse viral strains.[37] Unlike conventional antibodies, bnAbs require extensive somatic hypermutation and specific maturation pathways, which natural infection rarely elicits efficiently.[38] Novel vaccine strategies focus on engineering immunogens to initiate and guide the development of bnAb precursor B cells, addressing HIV's evasion tactics such as hypervariability and glycan shielding.[39] Germline-targeting approaches design immunogens to bind naive B cell receptors resembling unmutated bnAb ancestors, priming rare precursor lineages for subsequent boosting.[40] For instance, eOD-GT8 immunogens specifically activate VRC01-class bnAb precursors by mimicking the CD4-binding site epitope.[41] In nonhuman primate studies, germline-targeting vaccination induced neutralizing antibodies in germline-reverted models, demonstrating activation of bnAb lineages.[42] Human phase I trials, such as those evaluating BG505 SOSIP trimers modified for germline binding, have initiated to test safety and immunogenicity, with early data showing precursor B cell responses but limited breadth.[43] These strategies acknowledge the low frequency of bnAb precursors in humans, estimated at 1 in 10^5 to 10^6 B cells, necessitating precise epitope presentation.[44] Sequential immunization protocols administer a series of tailored Env immunogens to iteratively mature bnAb responses, mimicking the prolonged antigen exposure in elite controllers.[45] Preclinical models using nanoparticle-displayed trimers or stabilized SOSIP variants have elicited tier-2 neutralizing activity against autologous strains in rabbits and primates after multiple boosts.[46] A 2022 human trial demonstrated vaccine-induced heterologous neutralizing antibody precursors, marking proof-of-concept for rapid lineage activation.[47] However, achieving the 30-50% somatic mutations typical of potent bnAbs remains challenging, with probabilities of full maturation low without optimized sequencing.[38] Structure-based design leverages cryo-electron microscopy and X-ray crystallography to engineer native-like Env trimers that expose bnAb epitopes while occluding non-neutralizing sites.[48] SOSIP-stabilized trimers, such as BG505 SOSIP.664, adopt prefusion conformations and have been iteratively refined to enhance germline precursor affinity.[49] Recent advances include cyclically permuted gp120 trimers and computationally optimized variants that select for functional bnAb mutations during affinity maturation.[50] In 2024, engineered immunogens activated diverse bnAb precursors in animal models, improving epitope-specific responses.[51] Despite progress, clinical translation faces hurdles, including immunogen stability, delivery vectors like mRNA or adenoviral platforms, and the need for multi-epitope targeting to cover HIV's epitope diversity. Ongoing trials emphasize combinatorial regimens to broaden coverage beyond single bnAb classes.[52]Emerging Technologies (e.g., mRNA and Vector-Based Platforms)
mRNA platforms enable rapid encoding of HIV envelope (Env) immunogens to stimulate B cells, particularly through germline-targeting strategies that activate rare precursor B cells for broadly neutralizing antibodies (bnAbs).[53] In May 2025, data from two phase 1 trials (IAVI G001 and Fred Hutchinson's HVTN 133) demonstrated proof-of-concept for this approach, showing successful priming of VRC01-class bnAb precursors in humans using sequential mRNA immunogens like eOD-GT8 and Core-g28v2.[53][54] These trials involved 54 and 18 participants, respectively, with vaccines eliciting immune responses without severe adverse events, marking the first human evidence of targeted bnAb lineage activation.[55] Further advancements include membrane-anchored HIV Env constructs delivered via mRNA, tested in preclinical models and early human studies as of July 2025, which enhanced B-cell responses by stabilizing trimeric Env structures to mimic native virus.[56] An August 2025 phase 1 trial in Africa, sponsored by IAVI, began evaluating mRNA-1644 (eOD-GT8 60mer) and related boosters in 120 adults, including people living with HIV, to assess safety and immunogenicity for bnAb induction.[57] Germline-targeting mRNA strategies address HIV's shielding of conserved epitopes by iteratively boosting immature B cells toward mature bnAbs, with October 2025 research confirming simultaneous priming of multiple bnAb classes in animal models.[58] Viral vector platforms, such as adenovirus and vesicular stomatitis virus (VSV), deliver HIV genes to induce T-cell and antibody responses, leveraging self-adjuvanting properties for durable immunity.[59] Despite historical risks with adenovirus serotype 5 (Ad5) vectors—linked to increased HIV acquisition in the 2007 STEP trial due to CD4+ T-cell enhancement—newer serotypes like Ad26 and gorilla-derived GRAd mitigate pre-existing immunity and safety concerns.[60] In January 2024, ReiThera, the Ragon Institute, and IAVI initiated preclinical work on a GRAd vector encoding highly networked T-cell epitopes, advancing toward phase 1 for broad HIV control via cytotoxic T lymphocytes.[61] IAVI's VSV vector candidates target T-cell epitopes alongside Env immunogens, showing immunogenicity in phase 1 trials post-2020 without the integration risks of DNA platforms.[62] These vectors support multi-epitope designs for conserved HIV regions, with plug-and-play adaptability allowing rapid iteration against variants, as evidenced in 2025 reviews of recombinant viral chassis.[63] Combined mRNA-vector regimens are under exploration to synergize antibody priming with T-cell augmentation, though challenges persist in scaling bnAb maturation and avoiding vector-induced enhancement.[64]Clinical Trials and Outcomes
Phase I and II Trials: Safety and Immunogenicity
Phase I and II clinical trials of HIV vaccine candidates have evaluated safety in small cohorts of HIV-uninfected volunteers, followed by immunogenicity assessments in expanded groups to detect antibody and T-cell responses without measuring efficacy. These trials, numbering over 100 since the late 1980s, have consistently shown that most candidates—ranging from subunit proteins to viral vectors—are well-tolerated, with adverse events limited to mild-to-moderate injection-site reactions, fatigue, and transient fever in 10-50% of participants, and no vaccine-attributable serious events or HIV infections directly linked to immunization.[10] [65] The inaugural Phase I trial, launched in 1987 by the National Institutes of Health, tested a recombinant gp160 envelope subunit vaccine in 138 healthy volunteers, confirming safety through absence of serious adverse effects and inducing detectable HIV-specific antibodies, though responses were narrow and immunogen-specific without broad neutralization.[10] [66] Early 1990s Phase I/II trials of gp120-based vaccines, such as AIDSVAX B/E, administered at doses up to 600 μg, similarly demonstrated tolerability with primarily local reactogenicity, eliciting peak anti-gp120 binding antibody titers of 1:10,000-1:50,000 in 70-90% of recipients after three doses, but these waned within 6-12 months and targeted only homologous strains.[65] [67] From the mid-1990s onward, prime-boost strategies—often DNA priming followed by viral vector (e.g., canarypox ALVAC) or protein boosting—dominated Phase I/II evaluations, enhancing cellular immunogenicity over standalone approaches; for instance, ALVAC-HIV (vCP1521) plus gp120 trials in the late 1990s to 2000s induced IFN-γ-secreting T cells in 30-60% of participants and IgG responses, with regimens showing no excess safety signals beyond grade 1-2 events like headache in 20-40% of cases.[68] Adenoviral vector trials, such as those with Ad26 mosaics in the 2010s, reported comparable safety profiles and broader CD8+ T-cell responses targeting conserved epitopes in up to 80% of vaccinees, though antibody induction remained focused on non-neutralizing epitopes.[69] [70] Despite these advances, immunogenicity across trials has proven insufficient for sterilizing immunity, with humoral responses rarely exceeding 10-20% neutralization breadth against diverse HIV clades and cellular responses declining to baseline within 1-2 years, underscoring HIV's evasion via envelope shielding and hypervariability.[71] Recent Phase I/II efforts post-2010, including stabilized Env trimers and mRNA platforms, continue to prioritize safety while targeting germline B-cell activation for bnAbs, yielding higher-tier neutralization in subsets (e.g., 20-40% of participants) but still transient and low-magnitude compared to natural elite controllers.[72] This pattern of safe yet suboptimal immune elicitation has informed progression to larger trials, revealing no evidence of enhanced susceptibility in recipients.[73]Phase III Efficacy Trials: Successes and Failures
The first Phase III efficacy trials for HIV vaccines, conducted in the late 1990s and early 2000s, tested recombinant gp120 subunit vaccines but demonstrated no protective efficacy. Vax004, initiated in 1998 and involving 5,409 participants at higher risk in North America and Europe, used bivalent gp120 (B and E subtypes) with MF59 adjuvant; it failed to reduce HIV acquisition, with infection rates of 3.8% in vaccinees versus 3.3% in placebo recipients over 36 months.[74] Similarly, Vax003, conducted from 1999 to 2003 in Thailand with 2,454 injecting drug users, employed gp120 (B/E) with alum adjuvant and also showed no efficacy, as HIV incidence was comparable between groups (6.7 infections per 100 person-years in both).[74] These failures highlighted the insufficiency of gp120-based approaches in eliciting broadly protective immune responses against diverse HIV strains.[71] A landmark partial success emerged from the RV144 trial, conducted in Thailand from 2003 to 2009 with 16,402 low-risk adults. This prime-boost regimen combined ALVAC-HIV (vCP1521, a canarypox vector expressing gp120, gag, and protease from clades B and E) priming with AIDSVAX B/E (gp120 boost) and showed 31.2% vaccine efficacy (95% CI: 1.1-51.2; p=0.04) against HIV acquisition at 42 months, with efficacy peaking at 60% in the first year before waning.[71] No effect on viral load or CD4 counts was observed in breakthrough infections, and correlates analysis later linked reduced risk to IgG antibodies against V1V2 scaffold and low Env-specific IgA levels, suggesting a role for non-neutralizing antibodies in mucosal protection.[75] Despite its modest and transient protection, RV144 remains the only Phase III trial to date demonstrating statistically significant efficacy, renewing interest in poxvirus-vector strategies but underscoring the need for durable responses.[76] Subsequent trials targeting T-cell responses largely failed, often revealing unintended risks. The STEP (HVTN 502) trial, launched in 2004 with 3,003 HIV-uninfected men who have sex with men or at risk in North America and Europe, tested a Merck Ad5-gag/pol/nef trivalent vaccine; it was halted in 2007 after interim analysis showed no efficacy (hazard ratio [HR] 1.0 overall) and an increased infection risk (HR 2.3) among Ad5-seropositive, uncircumcised participants, attributed to vector-induced enhancement of HIV susceptibility via CD4+ T-cell targets.[74] The parallel Phambili (HVTN 503) trial in South Africa, using the same regimen in 801 participants, was stopped early in 2007 with no efficacy observed (HR 1.81 in early unblinded data), reinforcing Ad5 vector limitations due to pre-existing immunity.[74] HVTN 505, a 2010-2013 trial in 2,294 US men, employed DNA priming followed by Ad5 boosting (with env, gag, pol inserts); it failed to prevent infection or control viremia (HR 1.21) and was terminated early, further evidencing challenges in T-cell-focused designs against HIV's mutational escape.[74]| Trial | Start Year | Location/Participants | Regimen | Efficacy Outcome | Key Issues |
|---|---|---|---|---|---|
| Vax004 | 1998 | North America/Europe (5,409 high-risk) | gp120 (B/E) + MF59 | 0% (no reduction) | Narrow subtype focus; no broad neutralization |
| Vax003 | 1999 | Thailand (2,454 IDUs) | gp120 (B/E) + alum | 0% (no reduction) | Inadequate immune breadth in high-risk group |
| RV144 | 2003 | Thailand (16,402 low-risk) | ALVAC prime + gp120 boost | 31.2% (waning) | Modest success; V1V2 IgG correlate identified |
| STEP (HVTN 502) | 2004 | Americas/Europe/Australia (3,003 MSM/at-risk) | Ad5 gag/pol/nef | 0%; HR 2.3 in subgroup | Vector immunity-enhanced risk |
| Phambili (HVTN 503) | 2005 | South Africa (801) | Ad5 gag/pol/nef | 0% (HR 1.81) | Pre-existing Ad5 antibodies; early halt |
| HVTN 505 | 2010 | USA (2,294 MSM) | DNA prime + Ad5 boost | 0% (HR 1.21) | No impact on acquisition or viremia control |