A study led by researchers from the Scripps Research Institute, the University of Pennsylvania and Harvard Medical School shows that rhesus macaques (Macaca mulatta) can be prompted to produce neutralizing antibodies against one strain of HIV that resembles the resilient viral form that most commonly infects people, called a Tier 2 virus. Published in the journal Immunity, the study also provides the first-ever estimate of vaccine-induced neutralizing antibody levels needed to protect against HIV.
Scanning electron micrograph of HIV particles infecting a human T cell. Image credit: National Institutes of Health.
“We found that neutralizing antibodies that have been induced by vaccination can protect animals against viruses that look a lot like real-world HIV,” said Scripps Research’s Dr. Dennis Burton, co-lead author of the study.
Although the new vaccine is far from human clinical trials, the study provides proof-of-concept for the HIV vaccine strategy the researchers have been developing since the 1990s.
The goal of this strategy is to identify the rare, vulnerable areas on HIV and teach the immune system to make antibodies to attack those areas.
Recent studies have shown that the body needs to produce neutralizing antibodies that bind to the virus’ outer envelope protein trimer.
To support this idea, the scientists found that they could protect animal models from HIV by injecting them with neutralizing antibodies that were produced in the lab.
The challenge then was to get animals to make the neutralizing antibodies themselves. To do this, they needed to expose the immune system to the envelope protein trimer, effectively training it how to spot this target and produce the right antibodies against it.
But there was a big problem. The HIV envelope trimer is unstable and tends to fall apart when isolated. How could scientists use it as an ingredient in a vaccine? A breakthrough came in 2013, when they genetically engineered a more stable trimer, or SOSIP.
“For the first time, we had something that looked pretty much like the HIV envelope protein trimer,” said study first author Dr. Matthias Pauthner, also from the Scripps Research Institute.
Env protein-based vaccination strategies can protect against hard-to-neutralize SHIV challenge in rhesus macaques. Image credit: Pauthner et al, doi: 10.1016/j.immuni.2018.11.011.
The study authors quickly moved forward with designing an experimental HIV vaccine that contained this stable SOSIP trimer.
Their goal with the new study was to see if this kind of vaccine could actually protect animals from infection.
They tested the vaccine in two groups of rhesus macaques.
A previous study using the same vaccine had shown that some immunized monkeys naturally developed low neutralizing antibody titers (antibody levels) in their bodies, while others developed high titers following vaccination. From this study, the researchers selected and re-vaccinated six low titer monkeys and six high titer monkeys. They also studied 12 unimmunized primates as their control group.
The primates were then exposed to a form of the virus called SHIV, an engineered simian version of HIV that contains the same envelope trimer as the human virus. This particular strain of the virus is known as a Tier 2 virus because it has been shown to be hard to neutralize, much like the forms of HIV circulating in the human population.
The scientists found that the vaccination worked in the high titer animals.
The monkeys could produce sufficient levels of neutralizing antibodies against the envelope protein trimer to prevent infection.
“Since HIV emerged, this is the first evidence we have of antibody-based protection from a Tier 2 virus following vaccination,” Dr. Pauthner said.
“One question now is how can we get such high titers into every animal?”
The focus on titers became especially important as the researchers saw HIV protection wane as the high titers fell in the weeks and months following vaccination. In tracking the titers while continuously exposing animals to the virus, the researchers determined the titers needed to keep HIV at bay.
Importantly, the study also showed that neutralizing antibodies, but not other aspects of the immune system, were the key to stopping the virus.
“This is an important finding, since other labs have focused on the potential for T cells and other immune system defenses to block infection,” Dr. Pauthner said.
“Going forward, we are looking to improve the vaccine design for human trials and keep titers high. There are many immunological tricks that can be explored to make immunity last longer.”
The researchers are pursuing a strategy to elicit broadly neutralizing antibodies (bnAbs) that can neutralize many strains of HIV, rather than the single strain described in these studies.
“This research gives an estimate of the levels of bnAbs that we may need to induce through vaccination in order to protect against HIV globally,” Dr. Burton said.
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Matthias G. Pauthner et al. Vaccine-Induced Protection from Homologous Tier 2 SHIV Challenge in Nonhuman Primates Depends on Serum-Neutralizing Antibody Titers. Immunity, published online December 11, 2018; doi: 10.1016/j.immuni.2018.11.011
