HIV Vaccine Progress in the Context of a Decades-Long Struggle: What Are the Challenges?

ContagionContagion, August 2023 (Vol. 08, No. 4)
Volume 08
Issue 4


Despite a decades-long struggle to develop an HIV vaccine—one that is safe, effective, and immunogenic and provides durable protection—the goal remains elusive and has been fraught with several challenges. We hope to provide a brief overview of key HIV vaccine studies while navigating the challenges and achievements in the field of HIV vaccine development. This article will include studies evaluating vaccines for both prevention and management of HIV. Many factors contribute to the challenge of achieving an effective HIV vaccine:1-5

  • Wide viral genetic diversity and variability, particularly of the HIV envelope glycoprotein Env, a complex trimer with multiple antibody epitopes, which is a key target of neutralizing antibodies

Partly driven by errant reverse transcriptase

  • Immune escape: HIV that can evade immune responses (including neutralizing antibodies)

High mutation rates (estimated at 1-10 mutations per genome per replication cycle) and recombination

Broad conformational adaptability

Widespread glycan shielding of Env

  • Dissimilar animal models (eg, nonhuman primate, humanized mouse) used in preclinical studies
  • Certain vaccine platforms not viable for HIV because of risk of proviral DNA integration in host genome
  • Multiple components of immunity (eg, humoral, cell mediated) that need stimulation in vaccine design rather than a singular approach or methodology
  • Cost, feasibility, and investment
  • Growing repertoire and availability of effective biomedical HIV prevention approaches that pose challenges for vaccine trial recruitment

Multiple HIV vaccine clinical trials have been conducted globally over the past 35 years (FIGURE 1), including at various sites in Africa, the United States, Europe, South America, and Asia (including Thailand).1 Although these trials have been fraught with challenges, the lessons learned from the development of HIV vaccines have been helpful for the development of vaccines for other emerging infectious diseases, including COVID-19.4 We plan to discuss some highlights of important HIV vaccine clinical trials in this article.

The history of vaccine development has followed a logical approach over time. Given the optimism about the potential of broadly neutralizing antibodies to halt disease progression, initial studies were aimed at using vaccines as therapeutics. The first of these was the VaxSyn trial in 1987.1 This trial took place in the United States and studied the adjuvant recombinant envelope glycoprotein rgp160, created in a baculovirus-insect cell system for vaccine production, for management of HIV and to prevent progression of immunodeficiency among asymptomatic participants with HIV.1,6 Findings from the phase 1 study demonstrated the vaccine was safe and well tolerated.1,6 The 40-μg or 80-μg dose rgp160 vaccine recipients (at days 0, 30, 180, and optional day 540) had generally low serum antibody responses to HIV envelope proteins. Antibody titers were increased after the third dose but decreased over 18 months. A fourth dose of rgp160 led to homologous neutralizing activity and complement-mediated activity in some recipients.1,6 In other studies using a higher 640-μg dose of rgp160 vaccine, results demonstrated increased rates of homologous neutralizing antibody responses, although the titer was low and did not elicit sufficient neutralizing antibodies that were protective.1 Unfortunately, vaccine efficacy was not demonstrated because CD4 cell count reductions and disease progression were similar in vaccinated participants to those from the placebo group.1

Thereafter, results from longer-term studies performed over a period of 5 years similarly demonstrated stimulation of production of binding and neutralizing antibodies that were durable as well as CD4 responses. However, cytotoxic T-cell responses were lacking.1,7

The next logical step to address the concern for suboptimal T-cell responses was to use recombinant viral vector–based vaccines. One of the earliest was the HIVAC-1e vaccine, which was a recombinant vaccinia virus vaccine that expressed HIV gp160. In this early-phase clinical trial,8 healthy adult volunteers were randomly assigned to receive HIVAC-1e or control vaccinia virus.1,8 Findings from the study demonstrated that humoral and cell-mediated gp160 immune responses were elicited in some of the participants.8 However, the majority of participants had received the smallpox vaccine; thus, there was concern that preexisting immunity to a virus similar to the vaccine vector could diminish immune responses. This was suggested by results from another clinical trial of the same vaccine9 that found that 2 vaccinia-naïve participants who received HIVAC-1e boosted with an envelope protein demonstrated robust T-cell responses to virus and gp160 protein that were detected more than 1 year later, although this was not the case in those participants with vaccinia priming in the study. HIV envelope antibodies were developed in both participants.9 Results from this study also tested and supported the hypothesis that humoral response could be enhanced by a serial vaccine construct approach of prime vaccination with recombinant vaccinia vector expressing HIV-1 envelope followed by a booster vaccination with an envelope protein.1,9

A concern raised with viral vector–based vaccines for HIV was the potential for replication of viruses that could occur, particularly in immunocompromised individuals.1 Subsequently, nonreplicating poxvirus vectors were developed: attenuated vaccinia virus and canarypox (ALVAC).1 Thus, vaccine strategies shifted to nonreplicating or attenuated viral vectors in combination with recombinant envelope proteins administered (sequentially or in combination) as multiple doses to optimize immunogenicity.

In a clinical trial, the ALVAC-HIV vector vaccine vCP125 expressing gp160 was administered singularly or as a prime boost with adjuvant gp160.1,10 Findings from this study demonstrated that ALVAC-HIV led to neutralizing antibody response as well as cytotoxic T-cell activity.1 Other ALVAC vectors were developed to express HIV genes (eg, gag) to aid in wider-ranging cell-mediated immune response. Of note, vCP1521 was used as a prime vaccine in the RV144 vaccine trial conducted in Thailand.1,11 This was a randomized, multicenter, double-blind, placebo-controlled, community-based efficacy trial among individuals without HIV at risk for HIV infection. In this study, the priming recombinant canarypox vector vaccine ALVAC-HIV (vCP1521) at months 0, 1, 3, and 6, which was boosted with aluminum-adjuvant recombinant bivalent gp120 vaccine AIDSVAX B/E at months 3 and 6, was evaluated.11 The study was remarkable because it involved the largest number of individuals (16,395 participants without HIV) involved in an HIV vaccine trial at the time, and the study was powered to assess for efficacy.11 Findings from this study demonstrated vaccine efficacy of 31.2% (95% CI, 1.1%-52.1%) at 3.5 years post vaccination.1,11,12 This vaccine regimen generated HIV-specific humoral and cellular immunogenic responses.1 Several follow-up studies to the RV144 trial were conducted, including RV305 and RV306, with findings that ultimately demonstrated that late boosting (12 months post initial vaccination) could restore immune responses that declined after initial vaccination series. Thereafter, studies of other constructs that included viral vector encoding and recombinant proteins targeting specific HIV clades were conducted in regions where they predominate (eg, phase 1/2 HVTN 10013 and phase 2b/3 HVTN 70214 studies conducted in South Africa, although results from the latter study did not show efficacy in preventing HIV, leading to its early termination).

Other vaccine strategies that have been tested include the VAX003 (in men who have sex with men [MSM] and women) and VAX004 (in individuals who use injection drugs) trials that evaluated 2 aluminum-adjuvant bivalent recombinant gp120 vaccines based on their demonstration of protection in primates after HIV challenge.15,16 They were administered up to 30 months and found to be safe but not effective for the prevention of HIV.1,15,16

Furthermore, efforts were made to advance vaccines that expanded the breadth of vaccine antigens targeting multiple clades as well as diverse envelope proteins. A replication-defective adenovirus vector (eg, adenovirus serotype 5) encoding trivalent antigens—Gag/Pol/Nef—that researchers hoped would optimize T-cell–mediated immunity was also tested in the HVTN 502 and HVTN 503 studies.17,18 Unfortunately, both trials were terminated because of lack of efficacy. A multigene, multiclade (HIV-1 clade B Gag, Pol, Nef, and Env proteins from clades A, B, and C) vaccine delivered via DNA prime and adenovirus vector boost was tested in the HVTN 505 clinical trial.19 This study joined a long list of studies terminated early because of interim analyses demonstrating inefficacy of HIV prevention in vaccines. Notably, findings from the study demonstrated a higher number of breakthrough HIV infections in vaccine recipients.19 These clinical trials, although ineffective, provided important information about correlates of protection, such as antibodies against the V1V2 loop of gp120. Moreover, correlates of increased risk, such as IgA-binding antibodies to gp140, were identified.

More recently, other adenovirus vector–based vaccines that included 4 mosaic immunogens were evaluated with supplemental boosting by adjuvant proteins targeted to stimulate immune responses to a breadth of HIV strains. The HVTN 705/HPX2008 (Imbokodo, NCT03060629) trial evaluated the vaccine in cisgender women.20 Findings from this study demonstrated insufficient protection against HIV, and it was concluded in 2022. A sister study, the HVTN 706/HPX3002 (MOSAICO, NCT03964415) trial, evaluated the vaccine in transgender individuals and MSM; this study was terminated in early 2023 for lack of efficacy.21

Other studies have assessed passive immunotherapy using broadly neutralizing antibodies, such as VRC01, which targets the CD4 binding site on HIV envelope. The design of broadly neutralizing antibodies (bNAbs) has been optimized to allow for strategies such as epitope masking to enhance the production of neutralizing antibodies. VRC01 had been studied as passive immunotherapy for management and prevention of HIV.22 For HIV prevention, the HVTN 703/HPTN 081 and HVTN 704/HPTN 085 studies evaluated VRC01 in high and low doses for HIV prevention.23 Although results showed significant efficacy compared with placebo, there were fewer infections in the high-dose group. For infections with viral strains sensitive to VRC01, a protective efficacy was observed, suggesting that preventive efficacy was strongly correlated with the breadth of bNAbs. Future studies may include novel germline-targeting approaches that should simulate in vivo generation of bNAbs.24

Other novel approaches and strategies for vaccine development include vaccines expressing Tat, a viral transactivator of transcription protein,25 and cytomegalovirus-vectored vaccines that robustly stimulate CD8 T cells.26 Another approach is the DNA viral vector–adjuvant protein combination27 used in the PrEPVacc trial, which is evaluating the efficacy of 2 HIV vaccine regimens, DNA/AIDSVAX and DNA/CN54gp140 plus MVA/CN54gp140, compared with HIV preexposure prophylaxis (PrEP; tenofovir disoproxil fumarate/emtricitabine and tenofovir alafenamide/emtricitabine).1,28 This mixed approach also highlights the importance of potentially using HIV vaccines in addition to other strategies, such as PrEP, given the broadening array of available prophylactics for HIV prevention.3 Novel studies are also evaluating messenger RNA (mRNA) technology, a strategy that has been successful for COVID-19 vaccines in multiple HIV vaccine trials. For example, the HVTN 302 trial is evaluating 3 investigational HIV mRNA vaccines intended to present spike protein: BG505 MD39.3 mRNA, BG505 MD39.3 gp151 mRNA, and BG505 MD39.3 gp151 CD4KO mRNA.29 In addition, the clinical trial IAVI G003 studying the vaccine antigen eOD-GT8 60mer (for the mRNA-1644 vaccine candidate), a germline-targeting immunogen, is taking place in Rwanda and South Africa.30 Early results from both trials are expected in 2023. Although the mRNA platform holds promise to streamline the delivery system,5 it remains uncertain how the mRNA technology platform will affect immunologic response and clinical protection.3


There have been various approaches tested in the evaluation of an effective HIV vaccine; unfortunately, the reported data from various studies have fallen short. However, valuable lessons have been learned along the way, including that effective vaccines would likely have to stimulate broadly neutralizing humoral responses and effective T-cell immunity. Furthermore, certain correlates of protection and loss of protection have been identified. When drawing from the experiences of bNAbs and other studies, further work needs to be done to optimize the breadth of immunity (generated actively or delivered passively) to a virus that exhibits remarkable diversity. It will also be important to temper enthusiasm about immunogenicity data pending demonstration of clinical protection.

To sustain ongoing and future research, further coordinated, systematic efforts in the field of research and development of HIV vaccines in the pipeline are needed and may be performed in parallel; this was executed with COVID-19 vaccines during the COVID-19 pandemic.31 What is more, investment and support are needed because funding for an HIV vaccine has plateaued in the past several years.32 Sustainable networks, which include stakeholders, researchers, clinical trialists, advocates, and policy supporters, to support HIV vaccine development are fundamental to this development.31 Novel technologies, such as mRNA platforms for HIV vaccines, hold promise for advancements in the field of HIV vaccine development. However, the current era of multiple highly effective HIV prevention options that are now available globally will pose a challenge to the ethics and design of future clinical trials to assess HIV vaccine efficacy. In that context, approaches that include vaccines and approved biomedical prevention tools may be a way to enhance and achieve optimal protection against HIV.


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2.Laher F, Bekker LG, Garrett N, Lazarus EM, Gray GE. Review of preventative HIV vaccine clinical trials in South Africa. Arch Virol. 2020;165(11):2439-2452. doi:10.1007/s00705-020-04777-2

3.Hannah S, Chinyenze K, Shattock R, Yola N, Warren M. HIV vaccines in 2022: where to from here? J Int AIDS Soc. 2022;25(5):e25923. doi:10.1002/jia2.25923

4.Harris JE. The repeated setbacks of HIV vaccine development laid the groundwork for SARS-CoV-2 vaccines. Health Policy Technol. 2022;11(2):100619. doi:10.1016/j.hlpt.2022.100619

5.Morris L. mRNA vaccines offer hope for HIV. Nat Med. 2021;27(12):2082-2084. doi:10.1038/s41591-021-01602-4

6.Dolin R, Graham BS, Greenberg SB, et al. The safety and immunogenicity of a human immunodeficiency virus type 1 (HIV-1) recombinant gp160 candidate vaccine in humans: NIAID AIDS Vaccine Clinical Trials Network. Ann Intern Med. 1991;114(2):119-127. doi:10.7326/0003-4819-114-2-119

7.Birx DL, Loomis-Price LD, Aronson N, et al. Efficacy testing of recombinant human immunodeficiency virus (HIV) gp160 as a therapeutic vaccine in early-stage HIV-1-infected volunteers: rgp160 Phase II Vaccine Investigators. J Infect Dis. 2000;181(3):881-889. doi:10.1086/315308

8.Cooney EL, Collier AC, Greenberg PD, et al. Safety of and immunological response to a recombinant vaccinia virus vaccine expressing HIV envelope glycoprotein. Lancet. 1991;337(8741):567-572. doi:10.1016/0140-6736(91)91636-9

9.Graham BS, Belshe RB, Clements ML, et al. Vaccination of vaccinia-naive adults with human immunodeficiency virus type 1 gp160 recombinant vaccinia virus in a blinded, controlled, randomized clinical trial: the AIDS Vaccine Clinical Trials Network. J Infect Dis. 1992;166(2):244-252. doi:10.1093/infdis/166.2.244

10.Pialoux G, Excler JL, Rivière Y, et al. A prime-boost approach to HIV preventive vaccine using a recombinant canarypox virus expressing glycoprotein 160 (MN) followed by a recombinant glycoprotein 160 (MN/LAI): the AGIS Group, and l’Agence Nationale de Recherche sur le SIDA. AIDS Res Hum Retroviruses. 1995;11(3):373-381. Published correction appears in AIDS Res Hum Retroviruses. 1995;11(7):875. doi:10.1089/aid.1995.11.373

11.Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, et al; MOPH-TAVEG Investigators. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J Med. 2009;361(23):2209-2220. doi:10.1056/NEJMoa0908492

12.Robb ML, Rerks-Ngarm S, Nitayaphan S, et al. Risk behaviour and time as covariates for efficacy of the HIV vaccine regimen ALVAC-HIV (vCP1521) and AIDSVAX B/E: a post-hoc analysis of the Thai phase 3 efficacy trial RV 144. Lancet Infect Dis. 2012;12(7):531-537. doi:10.1016/S1473-3099(12)70088-9

13.Laher F, Moodie Z, Cohen KW, et al. Safety and immune responses after a 12-month booster in healthy HIV-uninfected adults in HVTN 100 in South Africa: a randomized double-blind placebo-controlled trial of ALVAC-HIV (vCP2438) and bivalent subtype C gp120/MF59 vaccines. PLoS Med. 2020;17(2):e1003038. doi:10.1371/journal.pmed.1003038

14.Gray GE, Bekker LG, Laher F, et al; HVTN 702 Study Team. Vaccine efficacy of ALVAC-HIV and bivalent subtype C gp120-MF59 in adults. N Engl J Med. 2021;384(12):1089-1100. doi:10.1056/NEJMoa2031499

15.Pitisuttithum P, Gilbert P, Gurwith M, et al; Bangkok Vaccine Evaluation Group. Randomized, double-blind, placebo-controlled efficacy trial of a bivalent recombinant glycoprotein 120 HIV-1 vaccine among injection drug users in Bangkok, Thailand. J Infect Dis. 2006;194(12):1661-1671. doi:10.1086/508748

16.Flynn NM, Forthal DN, Harro CD, et al; rgp120 HIV Vaccine Study Group. Placebo-controlled phase 3 trial of a recombinant glycoprotein 120 vaccine to prevent HIV-1 infection. J Infect Dis. 2005;191(5):654-665. doi:10.1086/428404

17.Buchbinder SP, Mehrotra DV, Duerr A, et al; Step Study Protocol Team. Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial. Lancet. 2008;372(9653):1881-1893. doi:10.1016/S0140-6736(08)61591-3

18.Gray GE, Allen M, Moodie Z, et al; HVTN 503/Phambili Study Team. Safety and efficacy of the HVTN 503/Phambili study of a clade-B-based HIV-1 vaccine in South Africa: a double-blind, randomised, placebo-controlled test-of-concept phase 2b study. Lancet Infect Dis. 2011;11(7):507-515. Published correction appears in Lancet Infect Dis. 2011;11(7):495. doi:10.1016/S1473-3099(11)70098-6

19.Hammer SM, Sobieszczyk ME, Janes H, et al; HVTN 505 Study Team. Efficacy trial of a DNA/rAd5 HIV-1 preventive vaccine. N Engl J Med. 2013;369(22):2083-2092. doi:10.1056/NEJMoa1310566

20.HIV vaccine candidate does not sufficiently protect women against HIV infection. News release. National Institutes of Health. August 31, 2021.

21.Janssen and global partners to discontinue phase 3 Mosaico HIV vaccine clinical trial. News release. Johnson & Johnson. January 18, 2023.

22.Bar KJ, Sneller MC, Harrison LJ, et al. Effect of HIV antibody VRC01 on viral rebound after treatment interruption. N Engl J Med. 2016;375(21):2037-2050. doi:10.1056/NEJMoa1608243

23.Corey L, Gilbert PB, Juraska M, et al; HVTN 704/HPTN 085 and HVTN 703/HPTN 081 Study Teams. Two randomized trials of neutralizing antibodies to prevent HIV-1 acquisition. N Engl J Med. 2021;384(11):1003-1014. doi:10.1056/NEJMoa2031738

24.Groundbreaking HIV vaccine design strategy shows promise in proof-of-principle tests. News release. Scripps Research. October 31, 2019.

25.Ensoli B, Moretti S, Borsetti A, et al. New insights into pathogenesis point to HIV-1 Tat as a key vaccine target. Arch Virol. 2021;166(11):2955-2974. doi:10.1007/s00705-021-05158-z

26.Abad-Fernandez M, Goonetilleke N. Human cytomegalovirus-vectored vaccines against HIV. Curr Opin HIV AIDS. 2019;14(2):137-142. doi:10.1097/COH.0000000000000524

27.A combination efficacy study in Africa of two DNA-MVA-Env protein or DNA-Env protein HIV-1 vaccine regimens with PrEP (PrEPVacc). Updated July 1, 2022.

28.Joseph S, Kaleebu P, Ruzagira E, et al. OC 8491 PrEPVacc: a phase III, MAMS adaptive prophylactic HIV vaccine trial with a second randomisation to compare F/TAF with TDF/FTC PrEP. BMJ Glob Health. 2019;4(suppl 3):A10. doi:10.1136/bmjgh-2019-EDC.23

29.NIH launches clinical trial of three mRNA HIV vaccines. News release. National Institutes of Health. March 14, 2022.

30.Cosdon N. First in-Africa clinical trial of mRNA HIV vaccine. Contagion. May 18, 2022.

31.Tatoud R, Snow W, Esparza J. A transformed global enterprise for an HIV vaccine. J Int AIDS Soc. 2021;24(suppl 7):e25822. doi:10.1002/jia2.25822

32.Investment by technology. Resource Tracking for HIV Prevention Research & Development. 2021.

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