2 Dec, 13 | by BMJ
Vaccines are among the greatest success stories in the history of individual and public health. Since the eradication of smallpox, the near eradication of polio, and control of several other infectious diseases, they have saved millions of lives and cost, and have boosted societal and economic progress. Yet for some pathogens, like HIV, with multiple ways to evade the immune system, past vaccine strategies have failed. Creating an AIDS vaccine will require solutions to both HIV specific and trans vaccinology issues impeding its development.
Researchers have made much progress toward an AIDS vaccine. Perhaps one of the greatest obstacles is HIV’s enormous genetic variability, which—due to safety concerns—eliminates a live attenuated vaccine, a strategy employed for many current vaccines such as measles, mumps, and rubella. Similarly, viral inactivation, successfully used for developing polio, influenza, and other vaccines, has slim chances for success, as the surface protein of HIV is highly variable. Simply inactivating the virus yields immune responses directed primarily at the variable regions of this protein and therefore targeting only one or a few of the many HIV variants.
HIV vaccine designers have thus devised a new strategy, termed reverse engineering or structure assisted vaccine discovery. Rather than simply attempting to weaken or kill the virus, they are combining recent advances in multiple disciplines to 1) identify rare HIV infected individuals who make broadly neutralizing antibodies against HIV, 2) identify the sites on HIV’s surface protein—known as the envelope protein or trimer—where these antibodies bind, 3) determine the molecular structure of these binding sites for such broadly neutralizing antibodies, and 4) design immunogens to mimic the structure of these binding sites to elicit such antibodies with a vaccine. Such immunogens can then be evaluated in preclinical and clinical studies for their ability to elicit desired immune responses and, ultimately, their ability to prevent and control HIV infection.
Beginning in 2009, researchers at the International AIDS Vaccine Initiative (IAVI) and other institutions have determined that only a small proportion of HIV infected individuals generate broadly neutralizing antibodies against HIV, and an even smaller subset of those individuals elicit both broad and potent neutralizing antibodies. This discovery led to scores of broadly neutralizing antibodies being isolated, and the identification of at least four major highly conserved regions on the envelope protein targeted by such broadly neutralizing antibodies. The molecular structures of these binding sites have now also been determined [1,2]. Moreover, these antibodies, when administered to non-human primates, were found to prevent infection of a hybrid simian-HIV (SHIV)—a proof that if such antibodies could be elicited by immunization, they would likely protect against HIV. Thus, the first three steps of the four step structure assisted vaccine discovery for HIV have largely been completed.
To achieve the final step—designing immunogens to elicit broadly neutralizing antibodies against HIV—significant advances have also recently emerged from different scientific disciplines. First, a crystal structure of the envelope trimer on the surface of HIV has been determined—a major feat as the trimer is a highly unstable assembly of proteins  . This advance enables scientists to understand at the molecular level how multiple broadly neutralizing antibodies interact with this structure and to begin designing next generation candidate HIV vaccines. Second, researchers have begun to unravel the complexities of the evolution of HIV broadly neutralizing antibodies in HIV infected humans, providing vaccine designers with their first look at how such antibodies are elicited  . Finally, using similar structure assisted vaccine discovery technologies, researchers achieved the final step for designing vaccine candidates against respiratory syncytial virus (RSV ), a major respiratory pathogen in infants, providing the first proof of principle for this rational vaccine design strategy.
If these advances in vaccine discovery strategies to elicit broadly neutralizing antibodies against HIV prove successful, they could lead to vaccines that prevent infection by the majority of the HIV variants globally. Together with other advances, including new approaches to elicit immune cells (T-cells) capable of killing HIV infected cells and the improvement of the first vaccine candidate that showed modest efficacy in Thailand in 2009 (RV144) in further efficacy trials in South Africa , this raises hopes that we can—and will—eventually develop effective vaccines against HIV. And with it, help put an end to a pandemic that has already claimed some 36 million lives and continues to infect over two million people every year. Furthermore, learnings from AIDS vaccine development will accelerate development of vaccines for other major global diseases, and vice versa. It is likely that the coming decade(s) will usher in another golden age of vaccinology, with significant benefits for both individual and public health, resulting in further progress for society.
Competing interests: I declare that that I have read and understood the BMJ Group policy on declaration of interests and I have no relevant interests to declare.
Wayne Koff is chief scientific officer at the International AIDS Vaccine Initiative (IAVI). Since 1999 he has overseen IAVI’s programs in AIDS vaccine research, discovery, and development. Koff has published more than 100 scientific papers and edited seven books on vaccine development, and was twice honored by the United States Department of Health and Human Services for developing innovative strategies to accelerate the development of AIDS vaccines.
1 McLellan et al. Nature. 23 Nov 2011. DOI: 10.1038/nature10696
2 Pejchal et al. Science. 25 Nov 2011. DOI: 10.1126/science.1213256
3 Lyumkis et al. Science, 31 Oct 2013. DOI 10.1126/science.1245627
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5 Wibmer et al. PLoS Pathogens. 31 Oct 2013. DOI 10.1371/journal.ppat.1003738
6 Liao et al. Nature 25 April 2013. DOI 10.1038/nature12053
7 McLellan et al. Science, 1 Nov 2013. DOI 10.1126/science.1243283