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.

“It’s an initial proof of principle but an important one, and we’re now working to optimize this vaccine design,” says the study’s senior author Richard Wyatt, Ph.D., a professor in the Department of Immunology and Microbiology at Scripps Research.

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.

The researchers analyzed the antibodies of the rabbit that had responded most strongly, and identified two distinct types of bnAb. One, which they called E70, blocks the CD4 binding site as expected, though in an unusual way—partly by grabbing one of the shielding glycans. The other, 1C2, hits a different but well known vulnerable spot on Env, at the interface between two key segments of the complex protein. The binding of antibody 1C2 apparently destabilizes Env so that it can no longer mediate HIV’s entry into host cells. That antibody also turned out to have an unusual breadth of neutralization, blocking 87 percent of a panel of 208 distinct HIV isolates.

The finding is an important demonstration that vaccination against HIV, if done in the right way, can achieve the goal of inducing bnAbs to multiple sites on the virus, Wyatt says.

The team of scientists are continuing to test and improve their vaccine strategy in small animal models and hope eventually to test it in monkeys and then humans.

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A US study using DNA-based and protein HIV vaccines in various combinations shows that antibody and a cellular immune response occurs within 6 weeks from the date of vaccination, and the combination must be administered together for the most rapid protection. This will enable more large-scale testing of the vaccine for effectiveness. About 40 million people today have HIV infections, and 1.2 million deaths a year are related to this infection.

The early phase trial was published in the Journal of Clinical Investigation on September 30, 2019. The vaccines tested the DNA-HIV-PT123 vaccine and the protein AIDSVAC® B/E vaccine. Different combinations of these were administered to four groups of patients being treated for HIV infection.

The trial, named HVTN 105, was performed by the HIV Vaccine Trials Network (HVTN). It was meant to advance the results obtained from the first vaccine trial to demonstrate any benefit from a HIV vaccine, the RV144/Thai trial conducted by the US Army.

Earlier research

The RV144 trial tested a vaccine containing a viral vector modified with HIV gag, protease and env genes, along with a recombinant gp120 protein (a glycoprotein antigen on the HIV envelope – AIDSVAX B/E), at months 0, 1, 3 and 6. Earlier protein-based vaccines failed to protect against the infection. The RV144, however, produced a primarily antibody-based response with about 30% and 60% protection against the infection at 3 months and one year respectively.

The presence of IgG2 antibodies against V1V2 region of the HIV envelope antigen gp120 was the most protective, and highest levels of this antibody were linked to a vaccine efficacy of over 60%. On the other hand, IgA levels were correlated with the risk of infection, perhaps because they prevent antibodies from recognizing antigens via their Fc domains. The presence of antibody-dependent cellular cytotoxicity (ADCC) and a low IgA titer is linked to a reduced risk of infection.

New directions in the current study

HVTN 105 was intended to investigate the benefit of a vaccine priming dose to enhance the benefits of the RV144 trial. The ALVAC viral vector was replaced by a DNA plasmid vaccine with the same genes but a different envelope antigen. The DNA plasmid offers several improvements compared to the ALVAC vector. DNA vaccines are more heat-stable, easier to manufacture, and more versatile in that they can be manufactured to contain different combinations of the HIV virus with or without adjuvants. Their safety profile in other vector vaccines has also been proved.

This combination of HIV DNA and protein vaccine has been tested in two small trials showing significant antibody and cellular immune responses. The current study is unique in showing the results of priming with a protein and using a DNA vaccine as a booster, and of using four doses of DNA vaccine, as well as being among the few trials to test the effects of giving these two products together from the first dose onwards.

The study

It included 104 patients who were not likely to be infected with HIV. The median age was 27 years, and 53% were male. They were randomly assigned one of four treatment groups. All were vaccinated intramuscularly at 0, 1, 3 and 6 months. T1 received a protein vaccine during the first two doses followed by DNA boosters for the next two doses. T2 received the doses in reverse order. The T3 group received HIV DNA for priming at months 0 and 1, with DNA and protein administered together as vaccine boosters for the next two doses. In T4, the two were given together for all four doses.

The outcome

The vaccines were generally safe and tolerated well. In all four groups, 80% to 100% of participants responded 2 weeks after the second dose of the protein vaccine. The highest response was in both T3 and T4 groups, where 95% to 100% of participants showed the production of antibodies against gp120, as well as V1V2. All the participants also showed T cell responses. The production of ADCC and neutralizing antibodies in response to the vaccine was seen at the highest levels in T3 and T4 respectively. The immune response was suboptimal when priming was done using the protein vaccine followed by DNA boosting. DNA priming with protein booster produced an immune response but below that achieved by the administration of DNA and protein together.  

The highest IgG3 production was seen in T3. The ratio of IgA to IgG with the T4 regimen was lower than with T3, and this is associated with a reduced risk of adverse effects. IgG4 production was unexpectedly high in the T4 group, a finding which requires more work to understand. CD4+ T cells were equally induced across all groups, but not CD8+ cells.

The importance of the study is its demonstration of a more potent induction of immunity by the coadministration of DNA with protein vaccine, compared to the moderate responses already seen in RV144. The presence of antibody and cellular responses to vaccination will help the vaccine to be tested on larger numbers of people to find its actual efficacy rate.

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