In a small phase 1 clinical trial, researchers show that an experimental two-dose HIV vaccine can induce crucial broadly neutralizing antibody precursor B cells in 97% of participants, without any significant side effects.
The findings of this first-in-humans evaluation, published in the December 2 issue of Science, represent an important first step in confirming a new vaccine strategy that could lead to an effective broadly neutralizing vaccine for HIV and other intractable pathogens that have eluded vaccine development, including coronavirus and influenza.
"At the most general level, the trial results show that one can design vaccines that induce antibodies with pre-specified genetic features, and this may herald a new era of precision vaccines," said William Schief, a researcher at The Scripps Research Institute and study co-author.
The human immunodeficiency virus, or HIV, is an infection that attacks the body's immune system, destroying white blood cells and weakening an individual's immunity against other opportunistic infections. In 2021, more than 38 million people were living with HIV worldwide.
Although there is no cure for HIV, antiretroviral medications have helped those with the virus to manage the illness and prevent disease progression. However, more than a million new infections occur globally each year, many of which are in regions that lack crucial medical and healthcare resources.
A preventative HIV vaccine is urgently needed to finally put an end to the global HIV/AIDS pandemic.
Building a better bnAb
Most effective vaccines teach a person's immune system to produce antibodies that prevent or reduce infection. In the case of HIV, a viable vaccine would need to train the immune system to detect and subsequently elicit antibodies that bind to the specific protein that HIV uses to infect a host's cells, which is often called the "spike" protein.
However, according to Schief, there are "hundreds of thousands or millions of HIV variants infecting humans," each with structurally complex and diverse spike proteins. Antibodies trained to interdict one variant of the virus may be entirely useless in preventing the vast majority of others.
A single vaccine that elicits the production of broadly neutralizing antibodies (bnAbs), which can recognize and target sections of the HIV spike protein that don't change as much, could provide a way to protect against the globally diverse strains of HIV. However, inducing HIV bnAbs through vaccination has proven impossible thus far.
"A small percentage of humans infected with HIV will produce very potent bnAbs," said Schief, "but it generally takes a long time — years — for bnAbs to develop during infection, and by that point the bnAbs can't help the person shake off HIV."
According to Schief, previous studies have shown that if bnAbs are present before an individual is exposed to HIV, they can prevent infection completely.
BnAbs require very specific genetic and structural features to seek out and bind to the molecular targets, or epitopes, on the surface of the virus's spike protein. To produce bnAbs, a vaccine strategy that can induce antibodies with pre-defined genetic and structural features is needed, said Schief.
One such strategy is called germline-targeting vaccine design.
Successful germline-targeting vaccine design involves a crucial first step: creating an a substance that generates an adaptive immune response, or immunogen, that targets and primes bnAbs-precursor b cells, which are rare antibody-producing immune cells with the necessary antibody and genetic features required to develop into bnAbs. Without these rare bnAbs precursors, the following steps in the vaccine strategy fail.
Schief and the researchers conducted the first-in-humans test of this important first step and developed a germline-targeting priming immunogen, eOD-GT8, which presented 60 copies of an engineered HIV spike protein containing mutations designed specifically to enhance its affinity to recruit bnAb precursors.
First in Human Evaluation
In a randomized, double-blind, placebo-controlled phase 1 clinical trial, they found that eOD-GT8 was safe and feasible and triggered responses from the bnAb precursors in 35 of the 36 vaccine recipients, and that the precursor responses were very strong within each.
According to Schief, the findings offer a proof of principle for the first step in the germline-targeting vaccine strategy.
"The next step is to determine if we can deliver a first boosting or shepherding immunogen after this priming immunogen to cause the bnAb precursors to mature further toward bnAb development," said Schief.
Complete validation of the germline-targeting vaccine strategy will only be achieved once researchers induce bnAbs in humans, which will be a critical milestone for HIV vaccine development and for the germline-targeting vaccine strategy itself, according to Schief.