By: I Wayan Adi Pranata, Adhella Menur

Why do we need preventive HIV vaccines?

Human Immunodeficiency Virus (HIV) is a retrovirus infecting the host immune system, particularly the CD4/ T-cell lymphocytes. It is classified into two main types: HIV-1 and HIV-2, which HIV-1 is more prevalent worldwide. Due to the obliterated immune cells, people living with HIV (PLWH) have faced challenges to maintain intact immune function to defend themselves from HIV and opportunistic infections. Since HIV infection became a global pandemic in 1981, the cases have continued to rise. In 2022, there were 39 million PLWH, and 1.3 million new infections occurred, leading to widespread health crises marked by significant morbidity and mortality. For more than three decades, antiretroviral therapy (ART) has been a cornerstone in controlling the HIV pandemic. ARTs suppress viral replication, significantly reducing the plasma viral load to undetectable levels (<50 RNA copies/mL). This suppression helps reconstitute the immune system and enhances PLWH’s quality of life. Long-life adherence to ART contributes to the growing number of PLWH with sustained viral suppression, which prevents the virus from spreading—embodied by the principle “undetectable equals untransmissible” (U=U). Although ART ceases HIV replication by targeting various stages in the HIV life cycle, it cannot eliminate the occult provirus incorporated into the host-cell genome. These la-tent proviruses can replicate and bounce back if ART is interrupted or stopped. Therefore, a cure for HIV is unattainable until this reservoir of latently infected cells is effectively eliminated. Consequently, there remains a critical need for comprehensive HIV prevention strategies, especially for high-risk populations (key populations).

Current valuable preventive measures for HIV infection include male circumcision, condom use, and ART as pre-exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP). These strategies work by reducing the initial virus exposure or limiting target cells for infection, contributing to a significant decline in new HIV cases. Hypothetically, the combination of ART and optimal preventive strategies may significantly reduce HIV transmission and end the pandemic – so why do we need HIV vaccines? Both ART and PrEP/PEP require a self-commitment to strict adherence, regular medical supervision, and sustained funding, which can be particularly burdensome in resource-limited settings where access to consistent medication and care can be challenging. Moreover, a substantial treatment gap remains, with untreated individuals continuing to spread the virus. ART also does not eliminate the virus or provide lasting immunity, and there is the threat of emerging resistant HIV strains and long-term health consequences. Therefore, developing an effective HIV vaccine that offers long-term immunity is crucial for further reducing new infections and potentially eliminating the virus. Vaccines would be a game-changer in the global fight against HIV, offering a cost-effective and scalable solution to prevent new infections and reduce healthcare costs. Furthermore, a successful vaccine could help mitigate the stigma associated with HIV, as it would symbolize a significant leap towards controlling and eventually eliminating the disease. Therefore, the development of an effective HIV vaccine is not just a scientific challenge but a public health imperative that holds the promise of a world without HIV/AIDS.

Why is it challenging to develop an effective HIV vaccine?

HIV vaccine development faces numerous biological hurdles to outsmart this rapid, shape-shifting virus. HIV has a high mutation rate during viral replication due to its error-prone reverse transcriptase, estimated to introduce 1–10 mutations per genome per replication cycle and easily escape antibodies. The virus also evades neutralizing antibodies by covering its surface (Env) with dense clumps of sugar molecules or glycan shields. Moreover, HIV exhibits extensive genetic variability both within and among populations. Another reason HIV is ahead of the game is its uniquely diabolical target-ing of immune cells and integrating its genetic material into them, which makes the virus invisible and prevents immune cells from sending the right signals to the orchestrated immune system. These complexities have rendered traditional vaccine development approaches ineffective in creating a vaccine that can provide reliable protection against HIV. The absence of a clear understanding of immune protection correlates also hampers HIV vaccine development. Since no individual has naturally cleared HIV to serve as a model of protective immunity, researchers lack a definitive blueprint for vaccine-induced immunity. Additional challenges in developing HIV vaccines include lacking suitable animal models. The non-human primate (NHP) challenge model, commonly used in virology research, has provided invaluable insights into HIV’s etiology but has not reliably predicted vaccine effectiveness in humans. One reason for this phenomenon may be that the challenge viruses used in these animal models are uniform and lack the complexity and diversity of HIV strains circulating among humans.

As we acknowledged, multiple safe and effective vaccines for the COVID-19 pandemic became available within the unprecedented timeframe of just one year. This rapid progress raises the question: why, after 30+ years, are we still awaiting an HIV vaccine? The swift development of SARS-CoV-2 vaccines was aided by prior research on related coronaviruses responsible for SARS and Middle East Respiratory Syndrome (MERS), as well as by advances in vaccine technology that had been refined over decades. Table 1 compares the vaccine development challenges between these two viruses.

Table 1. Comparison of the scientific barriers in HIV and SARS-CoV-2 vaccines development (adapted from Nkolola et al., 2023, doi: 10.1016/S2352-3018(23)00264-3).

The 30+ years of HIV vaccine development

In the late 1980s, the first approach focused on generating a vaccine that would induce neutralizing antibodies using a vaccinia vector (a recombinant HIV vaccinia virus) expressing gp120 or gp160 HIV-1 envelope proteins. This approach ended in 2003 after the trials produced poor results. In the early 2000s, the second approach was based on administering a viral vector (adenovirus serotype 5/Ad5) to induce a CD8+ T cell response. The goal of causing a CD8+ T cell reaction was to control post-infection viremia and potentially prevent HIV acquisition. This approach ended after the trials were terminated prematurely because of no efficacy. Potential limitations of this approach included the limited breadth of T-cell responses and pre-existing immunity to the Ad5 vector. The third approach utilizes a heterologous prime-boost to elicit humoral and cell-mediated immune responses. The prime-boost strategy is based on priming with a pox virus vector and boosting with a recombinant protein.

Table 2. HIV-1 clinical trials 1998–2024 (adapted from Nkolola et al., 2023, doi: 10.1016/S2352-3018(23)00264-3).

To date, only the Thai-RV144 trial has shown a modest efficacy of 31.2% 42 months after the final vaccination. This phase 3 efficacy trial tested AL-VAC-HIV, a recombinant canarypox virus vector vaccine incorporating Env (clade E), Gag (clade B), and Protease (pro) (clade B) components—serving as the prime. This was followed by a protein boost using AIDSVAX, which contained gp120 clade B from strain MN and strain A244 (from CRF01_AE), with alum as an adjuvant. The trial’s immune correlates analysis suggested that antibodies targeting the V1-V2 loop of gp120 might have contributed to the protection against HIV-1 infection. However, high levels of Env-specific IgA antibodies may have mitigated the effects of protective antibodies. The analysis failed to identify neutralization antibody as a potential correlate, but, surprisingly, the non-neutralizing antibodies, especially those involved in mediating antibody-dependent cell-mediated cytotoxicity (ADCC), may play a role in the protection. Currently, the increasing knowledge of which parts of the virus elicit broadly neutralizing antibodies (bNAbs) and the use of novel viral delivery platforms such as messenger ribonucleic acid (mRNA) have provided significant advancements in vaccine design.

Advance in HIV vaccine research: Lesson learned from recent clinical trials

The HIV-1 vaccine field is currently at a critical juncture with no candidates in efficacy trials due to the lack of success in recent studies such as HVTN 702, HVTN 705, and HVTN 706, along with challenges encountered in the PrEPVacc study. Hopes increased with further research on bNAbs – initially, the lack of evidence for antibody-mediated suppression of HIV in vivo led researchers to believe that the human body couldn’t produce antibodies to neutralize HIV. However, subsequent research identified a small group of people living with HIV, termed ‘elite neutralizers,’ who develop highly poent and broad responses many months or even years after infection. These antibodies, known as bNAbs, target parts of the virus that remain constant despite mutations, inhibiting the virus from entering the host cells, therefore preventing HIV integration into the genome. This discovery has shifted research focus towards two main prophy-lactic strategies: passive immunization, which involves infusing bNAbs directly into the body, and active vaccination, aimed at prompting the immune system to produce its own bNAbs, which later became more desired. Researchers have attempted to produce immunogens that induce the immune system, stimulating naive B cells to produce precursors to synthesize bNAbs.

Figure 1. The attempt to develop a promising vaccine that elicits potent anti-HIV bNAbs. Figure inspiration: the structural biolo-gy of HIV by; Watanabe Y, et al., 2020, doi: 10.1038/s41467-020-16567-0; Thavarajah JJ, et al., 2024, https://; and Suran M, 2023, doi:10.1001/jama.2022.23242. -Created with

Designed immunogens for HIV focus on the most conserved regions of the viral envelope glycoprotein (Env), including the CD4 receptor binding site (CD4bs), the gp120-gp41 interface, the V1V2 trimer apex, and the membrane-proximal external region (MPER). Advanced understanding has led to various innovative design strategies for HIV immuno-gens. These include targeting germ-line receptors to initiate specific immune responses by initially priming bNAb-precursor B cells and guiding their maturation with a series of specifically designed boosting immunogens. Other approaches stabilize the Env trimer structure through molecular designs like eOD-GT8, employ trimer mimics such as BG505 SOSIP.664 that closely resemble the Env spike, and develop epitope-targeted immunogens with minimal epitope fragments to precisely focus the immune response on critical regions of the Env spike while minimizing off-target effects. To guide the production of these bNAbs, an HIV vaccination regimen would likely necessitate additional (three to four) doses, each targeting a distinct strain of HIV. This implies that a slightly different immuno-gen must be administered with each shot, a complex process that represents the new frontier in HIV vaccine development.

In May 2023, findings from the IAVI G001 study, the first-in-human trial of a germline-targeting HIV nanoparticle vaccine, were published. The trial employed the protein immunogen eOD-GT8 60mer, combined with the adjuvant AS01B. This nanoparticle vaccine, based on the HIV-1 gp120 protein, was specifically designed to prime VRC01-class HIV-specific B cells, effectively increased the production of desired B cells in 35 of the 36 participants. This enhancement of B cell populations sets a foundation for subsequent booster shots designed to further stimulate these cells to produce HIV-protective bnAbs. Robust polyfunctional CD4+ T cells specific for EOD-GT8 and the lumazine synthase (LumSyn) component of eOD-GT8 60-mer were also induced after two vaccinations. Follow-up trials, including IAVI G002 and IAVI G003, are now utilizing Moderna’s mRNA technology to explore this promising vaccination approach further.

A recent study published from the HVTN 133 clinical trial on June 2024, sponsored by NIAID, has also provided proof of concept supporting the hypothesis that vaccines can induce bNAbs in humans. Williams and colleagues demonstrated that the gp41 MPER peptide-liposome immunogen could initiate polyclonal B cell lineages, including mature bNAbs and their precursors. Their findings revealed that 13 vaccine recipients generated early-stage MPER-directed antibodies after receiving two doses. Among the five participants who received three doses, two generated antibodies that neutralized 15% of global tier 2 HIV-1 strains and 35% of clade B strains in vitro. Furthermore, evidence of CD4+ T cell activity was observed in vac-cine recipients, an essential component for antibody development. Given those heartening results, that does not mean that HIV vaccines will be ready soon. It is estimated that approximately ten years (or hopefully sooner) will be required to demonstrate the consistent production of bNAbs. Researchers are confident that they are now on a promising track toward following the basic science and developing a multistep HIV vaccination regimen that guides the immune response and its stepwise phases in the right direction.

Table 3. Selected HIV-1 vaccine concepts in phase 1 clinical testing (adapted from Nkolola et al., 2023, doi: 10.1016/S2352-3018 (23)00264-3).

The recent success of mRNA vaccines for SARS-CoV-2 has highlighted mRNA as a promising vaccine delivery platform which allow quick modification. Key advantages of mRNA vaccines are their synthetic nature and straightforward manufacturing, enabling fast and flexible production, making them appealing for HIV-1 vaccine development. The difficulty with HIV is that it requires far more antibodies to prevent acquisition than SARS-CoV-2, up to 50 times more than SARS-CoV-2 vaccinations. Moreover, the durability of mRNA vaccines is limited, and they do not address the main scientific challenges of HIV-1 immunogen design, though they may accelerate the iterative testing of vaccine concepts. Several phase 1 clinical trial are now evaluating the safety and immunogenicity of various HIV-1 mRNA vaccines, mainly focusing on germline-targeting designs. The HVTN 302 trial is testing sequential immunization with BG505 MD39.3, BG505 MD39.3 gp151, and BG505 MD39.3 gp151 CD4KO mRNA vaccines. Another study is evaluating the eOD-GT8 60mer mRNA vaccine (mRNA-1644) and Core-g28v2 60mer mRNA vac-cine (mRNA-1644v2-Core). These trials will provide early data on the safety and immunogenicity of combining germline-targeting vaccine design with the mRNA platform.

Additionally, other new vaccine concepts focusing on HIV-1 cellular immunity have emerged. One promising approach uses cytomegalovirus (CMV) viral vectors, which can maintain high-frequency effector memory CD8+ T cells, including unconventional MHC-E-restricted CD8+ T-cell responses capable of arresting and clearing simian immunodeficiency virus (SIV). A phase 1a study is currently underway to test a CMV-based vaccine (VIR-1111) in humans. Another approach involves heterologous viral vector (HVV) vaccination, where multiple viral vectors are administered sequentially to induce high frequencies of CD8+ T cells in mucosal tissues, enhancing protection in the presence of neutralizing antibodies. Subsequent studies confirmed the durability of this protection, with animals resisting challenges months later and exhibiting robust antiviral responses. While T-cell vaccine candidates may not block infection entirely, they could control viral replication more effectively than central memory T-cell responses. Combining these strategies with bNAb vaccine candidates might offer the most effective protection against HIV-1.

Concluding remarks

Reflecting on the COVID-19 pandemic, it’s clear that individual prevention alone is insufficient, as it relies on people consistently making positive health choices (which is difficult!). They must be coupled with effective vaccination strategies to eventually end the pandemic. Modeling studies indicate that if current HIV treatment and prevention efforts continue and at least 50% effective HIV vaccine is developed and deployed, it could prevent millions of new infections. Recent years have brought about significant breakthroughs in HIV vaccine research, offering a glimmer of hope for enhanced prevention strategies to fight this shape-shifting virus and, ultimately, the cessation of the global pandemic.

We believe that effective vaccines could dramatically improve the prospects for eradicating HIV. As such, the pursuit of an HIV vaccine must remain a top priority, necessitating sustained funding and a global commitment. In the Journal of Virology commentary, Desrosiers RC shared the criteria for vaccine candidate: (i) elicit antibody responses capable of neutralizing most HIV strains circulating in the population; (ii) induce immune responses that are up/on/active for life, not just immunologic memory; and (iii) yield highly impressive protection against both homologous and heterologous virus challenge in valid animal models for AIDS.

Echoing Anthony S. Fauci’s viewpoint on the importance of HIV vaccines: To do anything less would lead to failure, which for HIV is not an option.


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