Virus World

Pan-betacoronavirus neutralizing antibodies may hold the key to developing broadly protective vaccines against novel pandemic coronaviruses and to more effectively respond to SARS-CoV-2 variants. The emergence of Omicron and subvariants of SARS-CoV-2 illustrates the limitations of solely targeting the receptor binding domain (RBD) of the Spike (S)-protein. Here, we isolated a large panel of broadly neutralizing antibodies (bnAbs) from SARS-CoV-2 recovered-vaccinated donors that target a conserved S2-region in the betacoronavirus spike fusion machinery. Select bnAbs showed broad in vivo protection against all three deadly betacoronaviruses, SARS-CoV-1, SARS-CoV-2 and MERS-CoV, that have spilled over into humans in past two decades. Structural studies of these bnAbs delineated the molecular basis for their broad reactivity and revealed common antibody features targetable by broad vaccination strategies. These bnAbs provide new insights and opportunities for antibody-based interventions and for developing pan-betacoronavirus vaccines.

Published in Immunity (Feb. 15, 2023):

https://doi.org/10.1016/j.immuni.2023.02.005 

An experimental HIV vaccine developed by scientists at Scripps Research and the nonprofit vaccine research organization IAVI has reached an important milestone by eliciting antibodies that can neutralize a wide variety of HIV strains. The tests, in rabbits, showed that these "broadly neutralizing" antibodies, or bnAbs, targeted at least two critical sites on the virus. Researchers widely assume that a vaccine must elicit bnAbs to multiple sites on HIV if it is to provide robust protection against this ever-changing virus. The promising results, which appear in Immunity, suggest that researchers are one step closer to developing an effective HIV vaccine--a major goal of medical science ever since the virus was identified in 1983. 

According to UNAIDS, about 35 million people worldwide have died of the immunodeficiency syndrome, AIDS, which is caused by HIV infection. About 38 million others are now living with HIV infection. Antiviral drugs can keep HIV-infected people alive and reduce their ability to transmit the virus to others, but these drugs do not clear the infection and must be taken indefinitely. Researchers have long recognized that a preventive vaccine, available at a low cost to uninfected people, will be needed to eliminate HIV as a major public health threat. HIV's rapid mutation rate and other mechanisms for evading immune attack have made it an extremely difficult target for vaccine designers. But the test conducted by Wyatt and his team confirms that vaccination can elicit the kinds of antibodies that are needed to provide broad protection against HIV. These bnAbs, as vaccine experts call them, can neutralize multiple HIV strains because they bind to critical sites on the virus that do not vary much from strain to strain. People who are infected with HIV sometimes produce bnAbs as part of their antibody response, but infrequently and usually after infection has been long established. The chief challenge for HIV vaccine designers has been to find ways to stimulate the immune system--in most or all individuals--into making bnAbs that hit multiple vulnerable sites on the virus, in order to protect against a high proportion of HIV strains.

At the heart of the vaccine design by Wyatt and colleagues is a virus-mimicking protein based on HIV's "Env" protein. Normally, multiple copies of bush-like Env proteins are spread out on the surface of each spherical HIV particle. Each Env protein contains a molecular mechanism that allows it to bind to a receptor on immune cells known as CD4, and use that receptor as a portal to break into the cell. The researchers engineered a version of Env that models the essential structures on the real Env while being stable enough to use as a vaccine. To present it in a way that would resemble a real HIV virus particle, they created virus-sized synthetic spheres of fat-related molecules, "liposomes," which are studded densely with the engineered Env proteins. On a natural HIV Env protein, thickets of sugar-related molecules called glycans normally help shield the all-important CD4 binding site from immune attack. As an initial "priming" immunization, the researchers used versions of Env in which this glycan shield around the CD4 binding site had been partly removed. "The idea was to better expose this site and thereby stimulate a broad antibody reaction to it at the start," Wyatt says.

Subsequent booster immunizations over 48 weeks used Env proteins with restored glycans, to select for antibodies that target the CD4 binding site but can also get through this shield. The Env proteins in the booster shots also were mixes based on different strains of HIV, to generally promote antibody responses against Env structures that do not vary among these strains. The team inoculated 12 rabbits following their vaccine strategy and compared the results with a control group that received only a single, glycan-shielded version of Env. They found that their vaccine strategy had a much better response, with five of the rabbits developing antibodies that could neutralize multiple HIV isolates...

Published in the J.  Immunology (Nov. 12, 2019):

https://doi.org/10.1016/j.immuni.2019.10.008

Investigators believe that an effective HIV vaccine would need to produce broadly neutralizing antibodies that would work on different strains of the virus. A phase 1 trial of a novel approach for HIV vaccination successfully stimulated production of rare immune cells needed to start the process of generating antibodies against the virus. Notably, the targeted response was detected in 97% of participants who received the vaccine, according to a press release. This study demonstrates proof of principle for a new vaccine concept for HIV, a concept that could be applied to other pathogens, as well,” said William Schief, PhD, whose laboratory developed the vaccine, in a press release. “With our many collaborators on the study team, we showed that vaccines can be designed to stimulate rare immune cells with specific properties, and this targeted stimulation can be very efficient in humans. We believe this approach will be key to making an HIV vaccine and possibly important for making vaccines against other pathogens.”

HIV affects more than 38 million people globally and is known to be one of the most difficult viruses to target with a vaccine. One of the major challenges is because the virus constantly evolves into different strains to evade the immune system. Investigators have worked for decades to create a vaccine that would stimulate the immune system to create rare but powerful antibodies called broadly neutralizing antibodies (bnAbs). According to the press release, bnAbs are specialized blood proteins that could attach to HIV spikes and disable them via important yet difficult-to-access regions that don’t vary much from strain to strain. “We and others postulated many years ago that in order to induce bnAbs, you must start the process by triggering the right B cells—cells that have special properties giving them potential to develop into bnAb-secreting cells,” Schief explained in the press release. “In this trial, the targeted cells were only about 1 in a million of all naïve B cells. To get the right antibody response, we first need to prime the right B cells. The data from this trial affirms the ability of the vaccine immunogen to do this.”

The strategy of targeting naïve B cells with specific properties is called germline-targeting, because these young B cells display germline genes. Investigators believe the approach could also be applied to vaccines for other challenging pathogens, such as influenza, dengue, Zika, hepatitis C virus, and malaria. The clinical trial, IAVI G001, enrolled 48 healthy adult volunteers who received either a placebo or 2 doses of the vaccine compound along with an adjuvant developed by GSK. According to the investigators, the novel design, the clinical trial, and the molecular B cell analyses provide a roadmap for further progress in an HIV vaccine. “This is a tremendous achievement for vaccine science as a whole,” said Dennis Burton, PhD, scientific director of the IAVI Neutralizing Antibody Center and director of the NIH Consortium for HIV/AIDS Vaccine Development, in a press release. “This clinical trial has shown that we can drive immune responses in predictable ways to make new and better vaccines, and not just for HIV. We believe this type of vaccine engineering can be applied more broadly, bringing about a new day in vaccinology.”

February 3, 2021:  https://www.scripps.edu/news-and-events/press-room/2021/20210203-hiv-vaccine.html.