The latest advances in the development of preclinical HIV vaccines

As researchers continue to find effective ways to fight HIV, but there is still no effective and approved preventive vaccine, vaccines are a key means to prevent the spread of HIV disease. There are 38 million people living with AIDS in the world, and many studies are devoted to developing effective methods to prevent the further spread of HIV. Here, we introduce the results of three studies, which have achieved satisfactory results in preclinical trials of HIV preventive vaccines.

Genetically engineered immune cells

A team of scientists from Scripps Research in the United States has discovered a new possible HIV vaccine method. In experiments involving mice, this strategy successfully induced broadly neutralizing antibodies (bnAbs) that can prevent HIV infection.

In previous work, Dr. James Voss and his team showed that CRISPR can be used to reprogram the immune system’s B cell antibody genes to produce the same HIV bnAb as in rare HIV patients.

This new study appeared in Nature Communications. The study showed that in mice, this engineered B cell, after being reintroduced into the human body, can proliferate after vaccination, and then mature and enter memory cells and plasma cells. And long-term production of high levels of protective antibodies. The team also demonstrated that using processes that occur in immune-responsive B cells can improve engineered genes to produce more effective antibodies against viruses.

“This is the first demonstration that modified B cells can produce a durable engineered antibody response in related animal models,” Voss commented. He hopes that his vaccine approach will one day prevent new HIV infections and may provide effective treatments for people already infected with HIV.

Voss said that in humans, the starting cells for the vaccine can be easily obtained by simply drawing blood, and then engineered in the laboratory before reintroducing them into the patient. He and his team are now exploring ways to improve the technology so that as many people as possible can use it. However, he pointed out that because the method relies on delivering genes to the patient’s own immune cells, this may be a major challenge.

Voss said: “People think cell therapy is very expensive.” “We are doing a lot of work to try to make this technology affordable as a preventive HIV vaccine or as a functional therapy that can replace daily antiviral therapy.”

Determine the best HIV antibody

A team from the Indian Institute of Science (IISc) reported a new rapid method for identifying specific regions on the HIV envelope (E) protein that can be targeted by antibodies. Researchers say this can be used to develop vaccines against HIV.

The research was led by Professor Raghavan Varadarajan and published in the Proceedings of the National Academy of Sciences.

To map the HIV-related areas, the researchers first used X-ray crystallography and cryo-electron microscopy (cryo-EM). However, they found that these imaging methods are time-consuming, complicated and expensive. Therefore, the team explored alternative methods and finally came up with a simpler but effective solution.

First, they mutated the virus so that the amino acid cysteine ​​appeared in multiple positions in the HIV E protein. Then, they added a chemical tag that would stick to these cysteine ​​molecules and treat the virus with neutralizing antibodies. If the antibody cannot bind to the key sites of the virus because it is blocked by the cysteine ​​tag, the virus can survive and cause infection. Those sites are then identified by sequencing the surviving mutant virus genes.

Varadarajan said: “This is a quick way to find out where the antibody binds and can be used for vaccine design.” He emphasized that it can also help test the response of serum samples from different patients to the same candidate vaccine or virus at the same time. “In principle, researchers can adapt this method to any virus, including SARS-CoV-2.”

Strengthen and sustain HIV prevention

Another study investigated how to use parts of the immune system that most vaccines cannot use to prevent HIV infection. Researchers from the Stanford University School of Medicine in the United States published a paper in the journal Nature Medicine that their findings have broad implications for immunologists for coronavirus vaccines and better vaccine procurement for other diseases.

Professor Bali Pulendran said: “Most vaccines stimulate serum immunity by raising antibodies against invading pathogens.” “This vaccine also enhances cellular immunity, gathering a large number of immune cells to catch up with cells infected by pathogens. We are here. A synergy is established between the two immune activities. We have shown that by stimulating the cellular arms of the immune system, you can get stronger protection against HIV even if the content of neutralizing antibodies is much lower.”

In their study, the researchers vaccinated three groups of 15 rhesus monkeys over a 40-week period. The first group received several consecutive inoculations with Env, a protein on the outer surface of the virus that is known to stimulate the production of antibodies, as well as an adjuvant. The second group also received a similar vaccination, but was injected with three different types of viruses. Each virus was modified to be infectious but not dangerous. Each modified virus contains an additional viral protein gene, Gag, which is known to stimulate cellular immunity. The third group, the control group, received only adjuvant injections.

At the end of the 40-week treatment course, all animals were rested for 40 weeks, and then only the Env vaccine was injected. After a four-week break, they were exposed to SIV (simian version of HIV) 10 times a week.

The research team found that monkeys that received only the adjuvant were infected. Animals in the Env and Env-plus-Gag groups received obvious initial protection from virus infection. Despite the lack of weak levels of neutralizing antibodies, several Env-plus-Gag animals (but no Env animals) remained uninfected.

The researchers further found that the protection period of animals using the Env-plus-Gag combination was significantly increased. After resting again, the six monkeys in the Env group and the six monkeys in the Env-plus-Gag group were further exposed to SIV. This time, four of the Env-plus-Gag animals remained uninfected.

Pulendran suspects that this improvement is produced by immune cells called tissue-resident memory T cells stimulated by the vaccine. These cells migrate to the location where the virus enters the body and remain in the body for a sustained period of time. If these cells get close to the virus again, they secrete factors that signal other immune cell types nearby, turning the tissue into a hostile area for the virus.

“These results indicate that future vaccination efforts should focus on strategies that elicit cellular and neutralizing antibody responses, which not only provide resistance to HIV, but also resistance to other pathogens such as tuberculosis, malaria, and hepatitis C virus. , Said Lawrence of the flu and pandemic coronavirus.