Broadly Neutralizing Antibodies: Key to an HIV Vaccine?

Recent Failures, New Research Paves the Way to Novel Strategies

IAVI_vaccine.jpg - Creative Commons https://www.flickr.com/photos/iavi_flickr/9317042700/sizes
Photograph © International AIDS Vaccine Initiative (IAVI)

Broadly neutralizing HIV antibodies (bNAbs) are defensive antibodies produced by the immune system, which is able to neutralize multiple strains of HIV. These antibodies are very rare in humans when compared to non-broadly neutralizing antibodies (or NAbs) that are specific to a single HIV strain.

There are currently over 60 different dominant strains of HIV-1 in the world, with a multitude of subtypes called recombinant HIV strains.

Since many HIV variants can exist within a single individual, developing an HIV vaccine has proven confounding to research since traditional vaccines trigger an antibody response that can neutralize maybe one or a few strains.

For a vaccine to be truly effective, scientists would need to develop an inoculant able to wipe out a vast array of HIV variants. This is why the discovery of bNAbs has become so central to current HIV vaccine design.

The bNAbs currently identified were isolated from individuals who demonstrated either have an innate immunity to HIV ("elite neutralizers") or the ability to avoid disease progression without the use of antiretroviral drugs ("long-term non-progressors").

Challenges and Setbacks in Vaccine Development

While a number of bNAbs have been identified as far back as 1993, the most potentially effective candidates were only isolated after 2009 (including some like VRC0-1 and VRC0-2, which are known to neutralize 90% of known variants).

However, the isolation of these antibodies doesn't mean that scientists can develop a vaccine able to spur a similar immune (humoral) response in the average individual. To date, we have not seen this, either for vaccines designed to protect against HIV or to prevent disease progression in those already infected with HIV.

What researchers have also found was that, outside of elite neutralizers, bNAbs don't necessarily function with similar effect in an immunized individual. While the bNAbs themselves have the ability to neutralize the virus, we have learned that is often difficult for them to penetrate the virus' outer coating (or "envelope").

Moreover, in people with HIV—for whom therapeutic vaccines are being explored—the humoral response is seen to wane over time. This may be explained by the fact that HIV infection, by its very nature, depletes the number of CD4 T-cells that initiate the immune defense. Without a robust CD4 response, it may be difficult to trigger the manufacture of bNAbs with sufficient or lasting impact.

And even if an adequate response is achieved, some research suggests that it may be one that develops over a long period, during which time the HIV population may have mutated to evade the antibodies' effects.

The Way Forward

Despite these obstacles, researchers are continuing to explore alternate or adjunct strategies, including the use of genetically engineered bacterium (the approach of which was shown stimulate insulin production in diabetics, for example) and even plant-based vectors (such as Agrobacterium tumefacien, which can deliver genetically modified DNA to human cells).

Others, meanwhile, are investigating whether combination vaccines and/or booster inoculations might improve efficacy, with some research suggesting that maturation of a protective bNAb response may take several years.

Increasing knowledge about bNAbs may ultimately pave the way to a multi-pronged strategy wherein multiple neutralizing agents may be employed. Among these are so-called "monoclonal antibodies" able to selectively target specific HIV variants, some of which have broadly neutralizing properties.

One of the more exciting discoveries centered around the N6 antibody, which in lab tests was able to neutralize 98% of all HIV strains. While it is uncertain whether these results will hold up on animal or human trials, it appears to be one of the most potent bNAbs yet isolated.

Sources

Gils, M. and Saunders, R. "Broadly neutralizing antibodies against HIV-1: Templates for a vaccine." Virology. January 5, 2013; 435(1):46-56.

Corti, D. and Lanzavecchia, A. "Broadly Neutralizing Antiviral Antibodies." Annual Review of Immunology. January 16, 2013; 31:705-742.

National Institutes of Health (NIH). "NIH Scientists, Grantees Map Possible Path to an HIV Vaccine: Co-Evolution of HIV and Strong Antibody Response Charted for First Time." Bethesda, Maryland; media release issued April 3, 2013.

Rosenberg, Y.; Sack, M.; Montefiori, D.; et al. "Rapid High-Level Production of Functional HIV Broadly Neutralizing Monoclonal Antibodies in Transient Plant Expression Systems ." PLOS|One. March 22, 2013; DOI: 10.1371/journal.pone.0058724.

Huang, J.; Kang, B.; Ishida, E.; et al. "Identification of a CD4-Binding Site Antibody to HIV That Evolved Near-Pan Neutralization Breadth." Immunity. November 15, 2016; 45(5):1108-1121; DOI: 10.1016/j.immuni.2016.10.027.

Continue Reading