35 years after the specific mechanisms and structure of the human immunodeficiency virus were first identified, the world is still waiting for a vaccine against HIV. Several late-stage candidates have failed in this time, leading to most of the major pharma companies exiting HIV vaccine research. Some new early-stage approaches hold major promise, but – as several leading global researchers told PharmaBoardroom – these projects will only reach fruition with intensive inter-stakeholder collaboration throughout the research, development, manufacturing, and marketing processes.
35 Years and Counting
People living with HIV have been waiting a long time for a vaccine. As Flavia Kyowukama of Ugandan patient advocacy organisation Action Group for Health Human Rights HIV/AIDS (AGHA) and herself a PLHIV expresses, “the slow progress of vaccine trials for HIV is a real frustration. We are left questioning how far the vaccine and cure trials have really advanced and when we will see the benefits. We are tired of the medication but have no choice but to continue taking it to continue living. Adhering to a pill-based treatment regimen for 21 years, as I have, takes a real heart and spirit.”
This disappointment was perhaps most keenly felt in 2020/21 when global public and private resources were effectively pooled to develop a vaccine for COVID-19 within a single year. While the COVID-19 virus proved considerably less complex and less prone to mutation than HIV, advocates for low- and middle-income countries were left questioning why they had to wait years to access these vaccines, as well as why similar amounts could not be dedicated to the fight against HIV.
“It is hugely frustrating that so much money was galvanised for COVID,” sighs Mitchell Warren of AVAC, a global HIV prevention advocacy group previously known as the AIDS Vaccine Advocacy Coalition. “When wealthy countries risked infection within their own borders, they were suddenly able to unlock billions of dollars. Clearly, for these countries, ‘Global Health’ means poor people in other countries.”
“The shocking amount of money thrown at the COVID crisis has never been made available for HIV, TB, or malaria,” laments Dr Linda-Gail Bekker, CEO of the Desmond Tutu Health Foundation, an HIV research and service institute in Cape Town, South Africa. “While HIV has received some funding, it has usually been from a single pharmaceutical company, the Gates Foundation, or the US National Institutes of Health.”
The role of HIV vaccine research in fighting COVID should also not be forgotten. “COVID vaccines themselves could not have been developed without the decades of scientific work on HIV vaccines and the accompanying infrastructure,” adds Birgit Poniatowski of the International AIDS Society. “The COVID trials themselves were run on the HIV trial sites. Our IAS Governing Council members, as infectious disease experts, were also leading the science on COVID-19, and so much has been learned through investments in HIV vaccine science.”
To add some context to the criticisms of the slow pace of HIV vaccine development, it is perhaps worthwhile to compare it to those for products aimed at other infectious diseases. It took just ten years following discovery of microbiologic cause to bring a vaccine for measles to patients and 16 years for Hepatitis C, but 47 years for polio and a full 105 years for typhoid.
Why Do We Still Need a Vaccine?
Given the drastic progress made in HIV prevention and treatment tools, detailed elsewhere in this report, why should public and private funders continue to pour money into HIV vaccine research that has thus far not yielded a single product?
For Bekker, the answer is simple. “We have never treated our way out of any infectious disease epidemic,” she notes. “Without a vaccine, we will always be chasing our tails for individuals who just got infected but avoided diagnosis or were not found in the system. This is particularly true of a disease like HIV that is often considered taboo, is kept undercover, and therefore lies latent for a long time. If we think we can treat our way out of it or that PrEP alone is enough to eradicate HIV, we are living in cloud cuckoo land.”
Dr Johan Vekemans, HIV vaccine product development team lead at IAVI, formerly the International AIDS Vaccine Initiative, agrees. He adds that “new treatment and prevention options have the potential to have an important impact on the epidemic and reduce the number of new infections. However, unfortunately, it is unlikely that these products really fit the needs of all world regions.”
Vekemans continues, “in 2022 alone there were 630,000 HIV-related deaths and 1.3 million new HIV infections. Even though the global trend is towards a diminution of HIV-related deaths and new infections, this is not the case everywhere …We cannot bve complacent and think that the job is done. Only a vaccine would really bring us to the goal of eliminating HIV as a global health problem. The other strategies need continued investments and continued health-seeking, and that is just not a very sustainable model.”
Complexity & Failures
January 18, 2023, marked a low point in the history of HIV vaccine development. Johnson & Johnson, considered the ‘last man standing’ among Big Pharmas working on HIV vaccines, was forced to abandon the Phase III trial of its candidate after an independent review found its vaccine regimen was not effective in preventing HIV infection compared to a placebo. Why has this field, which previously counted other vaccine luminaries like MSD (Merck in the US and Canada) and GSK, now been largely abandoned?
For Vekemans, “A lot of it has to do with scientific complexity, which has knock-on effects on funding strategies. The last 30 years have been marked by continuous learning about how complicated an undertaking an HIV vaccine is and, unfortunately, we have still not been able to bring a vaccine all the way to patients.”
He continues, “The HIV envelope protein, which is the target of many of the vaccine approaches, is covered by a ‘glycan shield,’ sugars hanging around the protein that hide it from the immune system. There are immunogenic areas of the protein that are displayed and accessible to the immune system, but the responses targeting these areas of the protein are not protective. Additionally, the HIV virus can rapidly hide within cells. Moreover, its DNA can integrate with human DNA, become latent and then reactivate later.”
“Initially, we went down the road of empirical research, similar to COVID,” elucidates Bekker. With COVID, the spike protein was an obvious immunogen, and we were lucky that the vaccines developed based on this worked effectively. With HIV, it is more difficult. We have not found the “Holy Grail” immunogen, and HIV is an incredibly mutable virus, constantly changing and escaping our attempts to control it.”
Hope Not Lost: The Search for Broadly Neutralising Antibodies
However, there are still several early stage, but highly promising HIV vaccine projects in the pipeline. These tend to follow the widely-adopted consensus that any HIV vaccine will need to generate what are known as ‘broadly neutralising antibodies (bNAbs).’ As Vekemans lays out, “Most vaccines against viruses work by inducing neutralising antibodies, but in the context of a hugely virally diverse disease like HIV, these neutralising antibodies need to be broadly protective. bNABs have been shown to develop, in a small minority of people living with HIV after long chronic infections.
“The field has now shifted from an empirical approach to a deductive one, focusing on bNAbs,” adds Bekker. “The antibody mediated prevention (AMP) studies [a major clinical study designed to test whether infusing bNAbs directly into individuals can prevent HIV infection – Ed.] have shown that if you have an antibody and a matching virus, even passive infusion of the antibody can prevent HIV.”
This move towards bNAbs is being supported by funding from the US National Institutes of Health (NIH), the major funder of HIV vaccine research today. NIH funding accounted for a full USD 591.6 million of the 731.7 million total research spend in 2022. As the NIH’s National Institute of Allergy & Infectious Diseases (NIAID)’s Director of the Division of AIDS (DAIDS) Dr Carl Dieffenbach notes, “There are several labs, both in the US and Europe, exploring these kinds of approaches and antibodies will end up being part of the next vaccine we test.”
Bringing a safe, effective, bNAb generating HIV vaccine to market is, however, by no means a given. “My concern is that we still do not know the required concentration of neutralising antibodies that target one of the five sites of vulnerability on HIV in a person who is vaccinated to achieve protection,” cautions Dieffenbach. “Based on the AMP trial, the concentration needed is a rather high level. The caveat “this will be good, but…” is what we need to pay attention to. By vaccination, will we be able to achieve concentrations antibodies directed against the sites of vulnerability of at least three bNAbs in people who have been vaccinated for enough time for the vaccine to have a protective effect?”
“It is important to note that we think we are going to need to target several epitopes on the HIV envelope viral protein and generate several classes of bNAbs to cover the spectrum of viral diversity,” adds Vekemans. “We are trying to generate complex immune schedules that will deliver several different immunogens in sequence, combined to target several target epitopes on the HIV protein. This approach, known as germline targeting, is one of the mainstream and priority approaches that the field is contemplating but there are others that also aim to generate bNAbs. Additionally, there are a few other approaches that aim to induce other types of protective immune responses, including T-cell vaccines and live attenuated viral constructs.
From Competitive to Collaborative
While cautioning that these bNAb-generating vaccine projects are still at a very early stage, Dr Dieffenbach does feel that the landscape is better primed for success than ever before. “The field has evolved from competitive to collaborative with a focus on sharing not just data, but innovative tools for vaccine evaluation in the preclinical space. That has changed the nature to very friendly competition with different actors driving each other to do better.” Indeed, one of the key ongoing projects is a seven-hander between mRNA vaccine pioneer Moderna, IAVI, Scripps Research, the Gates Foundation, NIAID, PEPFAR, and USAID.
“One of the greatest strengths of these kinds of partnerships is the democratisation of where the research gets done,” explains Dieffenbach. “What USAID brings to the table is world-class labs on the continent of Africa. The HIV Vaccine Trials Network brings their lab in South Africa as well. Andrew Ward at Scripps can use the microscope to determine the shape and structure of every antibody that binds to an HIV envelope within days of identifying it. Moderna can quickly make vaccine constructs that can go into preclinical for evaluation. The whole process is tightly iterative with immunogens being swapped between different groups around the world. These groups can take an immunogen which is known to induce a specific epitope, modify it slightly, and maybe add another epitope to another site on it.”
Also in South Africa, Dr Bekker and Glenda Gray, the outgoing president of the South African Medical Research Council (MRC), have recently received a significant grant from USAID to create the BRILLIANT (BRinging Innovation to cLinical and Laboratory research to end HIV In Africa through New vaccine Technology) Consortium, a multi-disciplinary collaboration led predominantly by African women scientists from Nigeria, Uganda, Kenya, Tanzania, Zimbabwe, Zambia, Mozambique, and South Africa. Over the next five years, it aims to discover and manufacture an immunogen on the continent, in collaboration with the mRNA hub currently being built by local biotech company Afrigen.
Bekker outlines that “Our current approach aims to coax our immune system to produce bNAbs – the best way to abort an infection – quickly. The mRNA platform makes this particularly exciting because we can iterate very quickly. You can introduce a new immunogen within six weeks, which is much faster than the years it took to build previous vaccine projects like adenovirus serotype 26 vector (Ad26) or Modified Vaccinia Ankara (MVA). This allows us to test and boost repeatedly, learning and improving along the way. This process is still at a Phase I early discovery stage, but it is hugely exciting. Once we figure out the prototype, subsequent vaccines will become easier to develop, similar to what we have seen with other vaccines.”
A Call to Arms for Pharma
Further collaboration, including with a currently disengaged group of Big Pharma players, will therefore be crucial to ending the long wait for an HIV vaccine. “Somehow, we need to convince the pharma companies who have fled the field to return by highlighting the necessity of a vaccine,” says Bekker. “Now, it is about pooling resources. Different entities need to bring their intellectual property, clinical trial sites, manufacturing platforms, or specialised researchers together. It is not easy science, as you must derive consensus and get everyone on board. There is a lot of time spent trying to achieve agreement, but hopefully, this process will get easier with practice.”
“Vaccine development requires at least some degree of an end-to-end perspective,” adds Vekemans. “From the offset, we need to have a vision of where the research will eventually lead and none of these questions are trivial. Concepts such as community engagement, understanding demand, public health need, user preference, product characteristics, and implementability, are vital to consider and are part of what drives the critical need for multi-stakeholder partnerships.”
Dieffenbach agrees, pointing out that even institutions of the NIH’s financial might cannot go it alone without industry input. “While it is possible to conduct discovery and advance molecules through Phase II trials independently, progressing to large-scale clinical trials and eventual market production requires the involvement of a pharmaceutical partner,” he states. “Such partnerships are essential for mass-producing a vaccine or drug and conducting the efficacy studies or further research needed to bring a product to market.”
