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Julie’s Biggest TakeawaysHIV 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.
“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 (thanks!)
- 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 and IgA Antibodies Elicited by Ad26 Vector Prime, Env Protein Boost Immunizations in Rhesus Monkeys.
- PLoS One: First-in-Human Randomized, Controlled Trial of an oral, replicating adenovirus 26 vector vaccine for HIV-1.
- HOM Tidbit: I am the Berlin Patient: A Personal Reflection.
- HOM Tidbit: Doctor who cured Berlin Patient of HIV: ‘We knew we were doing something very special’.
History of Micobiology Tidbit
Timothy Brown was diagnosed with HIV in 1995, but antiretrovirals helped control his infection. After becoming extremely exhausted while attending a friend’s wedding in 2005, he was diagnosed with acute myeloid leukemia. When he failed to respond well to chemotherapy treatments, his doctors, including hemotologist Gero Huetter, began to look for a donor. Not just any donor: Huetter searched through compatible donors for one who carried 2 copies of a gene called CCR5 delta 32. CCR5 is a coreceptor for HIV that helps the virus attach to and internalize into CD4 T cells, and the delta 32 mutation has a deletion that makes cells resistant to infection. Huetter needed to find a matching donor who carried 2 copies of this CCR5 delta 32 gene -- remember that our cells inherit one gene copy each from our mothers and from our fathers. A matching homozygous CCR5 delta 32 donor was found on the 61st attempt.
Brown’s treatment was not straightforward: his first chemotherapy was successful after all, and his cancer went into remission. After relapsing, he received his first stem cell transplant; the leukemia came back a third time and he underwent a second stem cell transplant, from the same CCR5 delta 32 donor. During his second and then his third remissions, he was tested for HIV and no trace of virus was found. The medical team searched his blood, intestines, brain -- basically every place that HIV might hide and that can be biopsied.
While he was being treated, Brown was known as The Berlin Patient, because he lived and was treated in Berlin. In 2010, Brown decided to release his name and to take interviews to raise awareness. In Brown’s words, “I did not want to be the only person in the world cured of HIV; I wanted other HIV+ patients to join my club.”
Brown’s name and story have since been well publicized - we’ll link to his firsthand account of being the first and thus far only HIV patient to be cured. What about the hematologist, Gero Huetter? His story is less well known. As a medical student in the 1980s, it was impossible for the HIV epidemic not to leave a strong impression on Huetter, and as a young hematology resident, it was reasonable that he would take note of a specific mutation that allows T cells to become resistant to HIV infection. When Huetter met Brown, an HIV positive patient with leukemia, he knew this was a potential opportunity to treat both diseases.
At that time, Huetter was unknown in the HIV research field, and the resulting report of the first cured patient took over a year for a medical journal to publish it. Once it was out, Huetter was inundated with emails from other HIV patients, who offered to pay anything for the same treatment. I should note here that success in the treatment was never guaranteed: irradiation alone, to remove the patient’s own immune cells, leaves the patient dangerously unable to fight infection, and rejection of the donor cells can add additional complications. The survival rate for a stem cell transplant is about 50%.
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