Quest for HIV Vaccine: Some Progress Despite Major Challenges

Dec. 21, 2020

Update: Results from the phase 2/B trial assessing mosaic vaccine safety and efficacy, described below, were released in 2021. The data demonstrated that the vaccine, while safe with no serious adverse events, did not sufficiently protect individuals against HIV infection (25.2% efficacy). A complementary phase 3 clinical trial assessing mosaic vaccine efficacy in men who have sex with men and transgender people (n= 3,900) yielded similar results: the vaccine was safe but did not protect against acquisition of HIV. Thus, the search for an effective HIV vaccine continues. 

Dan Barouch lays out the unique challenges of HIV vaccine development and discusses the ongoing clinical trial with a vaccine developed in his lab.

“HIV remains one of the defining epidemics of our generation,” according to Dr. Dan H. Barouch, M.D., Ph.D., in the ASM podcast “Meet the Microbiologist: HIV Vaccines with Dan Barouch.” Currently, more than 36 million people are infected, and nearly 2 million new infections occur annually. “Vaccines are historically the way viral epidemics are definitively ended,” said Dr. Barouch, who is a professor of medicine at Harvard Medical School and director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center. 

Despite the ample number of researchers developing HIV vaccines, results have been disheartening, with the best protection hovering around 30%. The challenges of developing an HIV vaccine are among the toughest in biomedical research.
One challenge is the lack of a proof of concept. There is no example of a patient’s immune response having cleared HIV that investigators could use to model a vaccine
A second challenge involves the speed with which HIV viruses can integrate themselves into the genomes of cells they infect, and the dormant, or latent state they assume once so integrated. Latent viruses may later re-emerge to infect other cells, but they are immune to antiretroviral therapy, and as yet, no-one has figured out how to expunge them.
Viruses become latent within the first few days after exposure to HIV. To prevent latency, a vaccine would have to generate an immune response still faster than that. Existing vaccines do not act that quickly. 
A third challenge is the HIV virus’s diversity. Replication of HIV is error-prone, and the mutation rate is high, especially in recently infected individuals, where it is 30 times higher than in chronically infected patients, according to an article in ASM’s Journal of Virology. The virus exists not as a single sequence, but as numerous different sequences both within the individual and throughout the world.
Thus, an HIV vaccine would need to induce an immune response to a diversity of viral sequences. One promising concept to address this diversity is a ‘mosaic vaccine’. Mosaic vaccines combine pieces from a wide variety of HIV viruses, to provide maximum coverage of the virus’ global diversity. 
The data — from both animals and humans — suggests that the resulting immune response can target multiple regions of multiple viruses, using both T-cell and antibody responses. 
Data published in July 2018 from a phase 1/2A (safety) study of a mosaic antigen vaccine in nearly 400 individuals in the U.S., East Africa, South Africa and Thailand showed that the vaccine was safe and induced an immune response.
The magnitude, the kinetics, the phenotype, and other properties of immune responses the vaccine raised in humans strongly resembled the immune responses it induced in animal models, which the investigators were able to test—successfully—for protective effect. (So far, there is no human data on whether that immune response will prove protective against HIV in humans.)
A larger study, a phase 2/B safety and efficacy study of this technology, commenced in sub-Saharan Africa late in 2018, with a goal of enrolling 2,600 individuals. Enrollment was completed in May, 2019, and the researchers announced completion of vaccinations at AIDS 2020.3
The study is a blinded, randomized, and placebo-controlled trial. Subjects were educated on risk-reduction strategies and advised that they should not expect that the vaccine will work until new data show otherwise.
The rationale for the location is that it has the highest HIV prevalence in the world, and thus would likely generate the most robust results.
During the podcast, the question arose as to what level of protection by vaccine could be considered a success. Dr. Barouch responded that a vaccine that had conferred a 31% level of protection had “led to many insights that have substantially impacted the research field and allowed [the] development of improved versions.…”
As for what level of efficacy would be considered successful, “I think the answer will change over time, and is also dependent on the degree to which the infection is still [at] epidemic levels,” said Dr. Barouch. “The degree of protection needed to have a major public health impact in sub-Saharan Africa might be very different from the efficacy needed for a major public health impact in the Western world.” 

Author: David C. Holzman

David C. Holzman
David C. Holzman, an award winning science and medical writer, has been writing for ASM since 1994.