HIV: the pursuit of an elusive vaccine

HIV has been a global health challenge for decades, affecting millions of lives around the world. In 2021, 1.5 million people became newly infected with HIV-1, and 650,000 people died from HIV-related illnesses [1]. Although advancements in long-lasting antiretroviral therapy (ART) have transformed HIV into a manageable chronic condition, 25% of people living with HIV still don't have access to treatment [1]. As ART is costly and only temporary, people who live in areas where healthcare is limited may not have access to the drugs or the healthcare professionals to administer them. Speaking to BioTechniques about the need for an HIV vaccine, Dennis Burton, Director at the Scripps Consortium For HIV/AIDS Vaccine Development (CHAVD; CA, USA), explained, “Antiretroviral therapies are great, but they are not the ultimate answer. There are issues with compliance, access and expense. A vaccine is the long-term solution to the HIV epidemic.”

Variability, glycans & latency

However, the quest for an HIV vaccine has been a bumpy, 40-year-long journey filled with challenges. One of the most significant challenges is that the HIV-1 virus evolves rapidly, exhibiting the highest recorded biological mutation rate currently known to science [2]. This is due to a combination of the error-prone nature of reverse transcriptase, which plays an important role in viral replication but has no proofreading ability, short generation times and recombination [2]. This results in extensive viral diversity both within and between hosts, making it difficult for the immune system to eradicate the virus and for researchers to develop therapeutics and vaccines that target it. “Although you could relatively easily make a vaccine against one strain of HIV-1, because there are hundreds of thousands of different strains, the vaccine would only be effective against that single strain,” explained Burton.

The high mutation rate of HIV-1 means that it has evolved ways to escape the immune system. The heavy glycosylation of HIV-1's envelope protein, Env, is the virus's primary method of immune escape. Env is on the surface of the virion envelope and is responsible for binding HIV-1 to its primary host receptor CD4, which mediates its entry into target immune cells [3]. As Env is the sole viral protein exposed on the surface, it is the target of host antibodies. To avoid being neutralized by antibodies, HIV-1 Env has evolved many glycan sites, making it one of the most heavily glycosylated proteins known, with nearly half of its mass consisting of host-derived glycans [3]. The glycans create a shield around Env that prevents antibody recognition and binding, as the host-derived glycans make it appear less like a foreign invader and are difficult for antibodies to grasp, and this presents issues for antibody-based vaccines.

Another challenge is HIV latency. HIV-1 quickly integrates itself into host chromosomes, and in some CD4⁺ T cells it remains latent and essentially invisible to the immune system and can re-emerge from these cells at any time in the future. This is why ART is not able to eradicate HIV-1 – once therapy is stopped, the latent virus can re-emerge and reinfect the individual [4]. As latency is established within the first weeks of infection, HIV-1 is only vulnerable to eradication for a very short amount of time. This means that vaccine candidates have to elicit an immune response that can eradicate the virus during the first few weeks, before latency is established. This has proved difficult, particularly for T-cell-based vaccines, as in the time it takes for a T-cell response to control the virus, the virus has already seeded itself in cells throughout the body. As Burton explained, “The T-cell response really requires that the virus has already infected cells. You need a certain level of infection before the immunity kicks in and squashes the infection. In the time that it takes for a T-cell response to really control the virus, the virus has already seeded itself in many different cells throughout the body and essentially, it's too late.”

The shift to broadly neutralizing antibodies

For these reasons, both classic antibody and T-cell vaccines have been difficult to develop for HIV-1, so the field shifted in a new direction: broadly neutralizing antibodies (bnAbs). bnAbs are naturally occurring antibodies that can neutralize many different strains of the virus. Unlike non-bnAbs, which target unique epitopes, bnAbs target conserved regions of Env, which remain unchanged when the virus mutates and are therefore found across strains, overcoming the variability challenge [5]. Studies have indicated that bnAbs develop in approximately 10–25% of individuals chronically infected with HIV-1 [6]; however, they constitute only a minor component of an individual's HIV-1 antibody response [7]. When passively administered, studies have demonstrated that bnAbs can prevent HIV-1 acquisition against bnAb-sensitive viruses and help treat established infection, but, similar to ART, protection is temporary and bnAbs would need to be administered periodically [8,9]. So, we know that the body can make bnAbs and that at high enough levels they can potentially prevent and treat HIV-1 infection, so the question now is: how can we induce the immune system to make them?

bnAbs arise when an infected individual is exposed to different strains of the virus, so antibodies evolve to recognize structures that are exhibited across different HIV-1 strains. At Scripps CHAVD, they are trying to reproduce this process using a set of sequential immunogens that can induce HIV-1-targeted bnAbs with an approach called germline targeting. The germline-targeting approach aims to elicit the production of bnAbs by stimulating rare ‘naive’ or ‘germline’ B cells that are capable of maturing into cells that make bnAbs. Contact with priming immunogens will activate target germline B cells, and subsequent exposure to structure-guided boost immunogens will shepherd the response along the pathway to bnAbs [10]. The group are currently investigating five different sites of vulnerability on Env that bnAbs bind to and hypothesize that a successful vaccine will induce bnAbs to target at least two sites by sequential administration of three to four immunogens.

To investigate and develop the immunogens, lots of different techniques and technologies are required. First, single-cell technologies are used to ‘mine’ bnAbs from infected individuals, and then cryoEM and crystallography are used to determine the structure of the antibodies in complex with Env [10]. These structures are fed into computational and artificial intelligence tools, which suggest structures for the shape on the virus that the antibodies bind to. Vast libraries of those suggested shapes are generated using yeast or mammalian display, and then the shapes that are best recognized by the bnAbs are selected as immunogens [10]. The selected immunogens are tested in animal models, including non-human primates and, as non-human primates don't make the same antibodies as humans, knock-in mouse models, which are mice that have been engineered via CRISPR-Cas9 to make human antibodies [10].

Promising results

The group have had success with their strategy so far, working with scientists at the International AIDS Vaccine Initiative (IAVI; NY, USA) and the Ragon Institute (MA, USA) to conduct two preclinical studies that validated their germline-targeting approach. The first study used bioinformatic analyses to assess the frequencies of bnAb precursors in healthy donors and found the two bnAbs with the most frequent precursor B cells, which meant they could design an immunogen to target those bnAb precursors [11]. The next study tested the new priming immunogen in knock-in mouse models and found that it could successfully bind and induce the target precursor cells [12].

The approach has now moved to humans, with the IAVI G001 Phase I clinical trial. The IAVI G001 trial, which included 48 healthy individuals, assessed the safety and ability of a different priming immunogen to induce responses from bnAb precursor B cells. The trial showed that the vaccine had a favorable safety profile and induced bnAb precursor B cells in 97% of people who were vaccinated [13]. To ensure that the vaccine is viable from a manufacturing perspective, the group have collaborated with scientists from Moderna (MA, USA) to formulate their immunogens into mRNA vaccines. This approach proved successful in mice, inducing a stronger antibody response than the protein-based vaccine formulation [12], and is now being tested in ongoing Phase I clinical trials.

“We are very excited because the IAVI G001 trial showed this approach works in humans. Now we have to develop and trial the other stages and replicate this with different sites on the virus. Our ongoing strategy for the next few years is to get the sequential immunogen approach into humans and see how it works. We have got lots of clinical trials planned for the next few years,” commented Burton.

Hope yet for T-cell vaccines

Although there has been a shift towards bnAb vaccines, there is still success to be found in other approaches. For example, a vaccine candidate developed by Louis Picker's group at Oregon Health and Science University (OR, USA) protected 55% of rhesus macaques from SIV infection, the non-human primate equivalent of HIV [14]. The candidate, called VIR-1111, uses the unique cytomegalovirus vaccine platform, which integrates tiny bits of the target pathogen into a weakened form of a herpes virus called cytomegalovirus. In monkeys, this triggers an unusual type of CD8⁺ T-cell response called an MHC-E-restricted T-cell response, which can effectively target SIV [15]. VIR-1111 is now being trialed in a first-in-human Phase I trial testing safety, reactogenicity, tolerability and immunogenicity; however, the results are yet to be released [16].

“At the moment, in monkeys, the vaccine is only partially effective. One of the most interesting strategies for the future is to try and bring broadly neutralizing antibodies together with Picker's T-cell vaccine,” commented Burton about the approach.

While nearly four decades of research are yet to deliver an effective HIV vaccine, the insights derived from this research have been invaluable to immunology, infectious disease research and vaccine development. Although it may still be some time away, current approaches and projects offer hope for an HIV vaccine.

With special thanks to Dennis Burton, who joined me in an interview to provide his expertise on HIV vaccine development and the research at Scripps Consortium For HIV/AIDS Vaccine Development (CA, USA).