Why have scientists struggled to generate a protective HIV vaccine? Dan Barouch lays out the unique challenges and discusses the ongoing clinical trial with an adenovirus-based vaccine developed in his lab. Julie’s Biggest Takeaways HIV poses unique and unprecedented challenges for vaccine development including: Viral diversity: extremely wide range of viral diversity. No natural precedent: No human has cleared HIV based on their immune responses. Unknown correlates of protection: scientists are unsure what immune responses are important to induce. Barouch’s group uses a vaccine strategy comprised of computationally optimized mosaic HIV Env proteins, which represent pieces of the outermost glycoprotein, Env, that have been tied together in a way expected to generate protective immunity. Early data from animal and human trials suggests these mosaic antigens generate an immune response to a wider array of HIV types than previous vaccines. Clinical trials are ongoing to see if a strategy of mosaic antigen vaccination, followed by a boost with Env protein, is protective in people. Attenuated HIV hasn’t been used as a vaccine strategy because of fears it could revert to a disease-causing form; similar fears have prevented a whole-killed virus platform for vaccine development. A clinical trial testing safety in 3 locations around the world demonstrated that this vaccine strategy in people elicited immune responses shown to be protective in animals. An efficacy trial is ongoing in sub-Saharan Africa, with results expected in 2021. The trial is double blinded: neither the doctor nor the patient know who was administered the candidate vaccine or who was administered the placebo. HIV latent infection causes complications in vaccine development because HIV latency is seeded early, possibly in the first few days of infection. Once latency is established, the individual is infected for life. Any low level of HIV infection in vaccinated people could potentially seed this latent infection. Quickly-seeded latency means immune responses must react extremely quickly. Featured Quotes “The challenges in the development of a prophylactic HIV vaccine are among the toughest challenges in biomedical and scientific research.” “HIV poses unique challenges for vaccine development and truly unprecedented challenges that have never been posed before by vaccination. One such challenge is the viral diversity: HIV exists not as a single sequence, but as numerous different viral sequences — not only throughout the world, but also throughout regions, communities, and even within the same individual. So to create a vaccine against HIV, the immune responses have to be relevant for a vast diversity of viral sequences.” “At what efficacy level would an HIV vaccine be licenced by both the industry partners as well as the government regulators in a particular country, and at what level of efficacy would it actually have a major public health impact? It’s a moving target over time; it really depends on what the current state of the epidemic is at the time the vaccine is ready to be licensed.” “It’s critical to have high-quality research part of the clinical efficacy trials so that success or failure or something in between, that the HIV research field learns from it, and learns what worked well and what didn’t work well, and how to make better vaccines moving forward.” “I always encourage young scientists to pursue their dreams and to tackle hard problems. There’s a lot of easy problems to solve but some of the hardest problems are the most impactful in the end.” Links for This Episode MTM Listener Survey Barouch lab at the Center for Virology and Vaccine Research. MTM: Mark Connors. The Lancet: Evaluation of a Mosaic HIV-1 Vaccine in a Multicentre, Randomised, Double-Blide, Placebo-Controlled, Phase 1/2 a Clinical Trial (APPROACH) and in Rhesus Monkeys. The Lancet: A Step Forward for HIV Vaccines. Journal of Virology: Similar Epitope Specificities of IgG an