Vaccine research and development work without success, new drug therapies continue to appear

For 40 years of fighting against "AIDS", there are setbacks and new hopes

  Many long-acting preparations for the treatment of AIDS have been on the market in the world. They can reduce the frequency of administration and allow the drug to exert long-term effects in the human body.

In addition, broad-spectrum neutralizing antibodies have also been found to have the ability to capture multiple strains, inhibit virus replication in patients, and effectively reduce HIV levels in humans.

  ◎Reporter Jin Feng

  December 1 is the 34th "World AIDS Day." During the 40 years of fighting against HIV, with the continuous deepening of research and the continuous advancement of medicine, mankind has achieved certain results in the fight against AIDS. Facing a huge challenge.

  Highly effective antiretroviral drugs have transformed AIDS from a fatal disease to a chronic disease that can be treated but is still incurable; broad-spectrum neutralizing antibodies that can block HIV cells before they are infected have begun clinical treatment Experiments and explorations; however, researches on AIDS vaccines have been "difficult to give birth" and have failed.

  The use of long-acting preparations to suppress AIDS is a trend

  "AIDS virus (HIV) specifically infects the human body's CD4+ T lymphocytes, thereby destroying the body's immune function, and promoting a variety of complications, such as various bacterial, fungal or viral infections and blood system tumors." Nanjing Medical Department Tang Huamin, a professor in the Department of Immunology at the University and a doctoral supervisor, told the Science and Technology Daily that in recent years, with the application of highly effective antiretroviral drugs, AIDS has transformed from a lethal disease to a chronic disease that can be treated but is still incurable. .

  "Currently highly effective antiretroviral drugs can be divided into 7 categories, including nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, fusion inhibitors, and CCR5 inhibitors. Drugs and drugs with new mechanisms of action.” Dong Li, chief physician of the Department of Infectious Diseases, Jiangsu Provincial People’s Hospital (the First Affiliated Hospital of Nanjing Medical University), told a reporter from Science and Technology Daily that because AIDS patients need to take medicine for life, it is often accompanied by viruses that are prone to drug resistance. , Patient compliance is extremely poor and other issues.

  "The use of long-acting agents to suppress AIDS is the future development trend." Fu Gengfeng, director of the Jiangsu Provincial Center for Disease Control and Prevention, explained that if AIDS patients do not take medicines on time and as required, the blood concentration in the body will be insufficient. The virus inhibition rate is reduced.

Once the virus accumulates, mutates, and the number increases, drug resistance will develop.

Long-acting preparations can reduce the frequency of administration, allow the drug to exert long-term efficacy in the human body, and also help improve patient compliance.

  At present, many long-acting preparations for the treatment of AIDS have been on the market in the world, such as cabotevir and ripavirin.

The former is an HIV integrase inhibitor, and the latter is a non-nucleoside reverse transcriptase inhibitor. The two can be made into long-acting injectable nanosuspensions.

In March 2020, the long-acting injections of Cabotevir and Ripavirin were approved for marketing in Canada, making it the world's first long-acting AIDS injection program on the market.

  Aikening is a synthetic peptide drug designed to target the HIV membrane protein gp41. It is the world's first approved long-acting HIV fusion inhibitor. It can be administered intravenously once a week and was approved in my country in August 2018 On the market, suitable for combined use with other antiretroviral drugs.

  "However, these long-acting preparations are only used as therapeutic drugs, and there are no long-acting drugs for pre-exposure prevention for people at high risk of AIDS." Fu Gengfeng said.

  But not long ago, ViiV Healthcare, a subsidiary of GlaxoSmithKline, announced that the U.S. Food and Drug Administration (FDA) has granted priority review qualifications for its new drug application (NDA) for cabotwe.

The company revealed that if approved, Cabotvir will become the first long-acting drug for the prevention of human immunodeficiency virus (HIV) before exposure to high-risk groups.

  AIDS vaccine research and development faces multiple challenges

  "Since the first case of AIDS was discovered in 1981, mankind has realized that the AIDS vaccine is one of the most effective means to end the AIDS epidemic. Unfortunately, there is no effective AIDS vaccine currently in clinical application," said Tang Huamin.

  In 1981, humans first discovered and reported AIDS, and the AIDS virus was isolated two years later, but since then, vaccine development has been stagnant.

In 1998, a company in the United States initiated the first large-scale AIDS vaccine trial, but declared the vaccine ineffective in 2003; the 2007 "STEP" project found that the AIDS vaccine HVTN 502 may increase immune cells after promoting immune cells to attack HIV. Risk of HIV infection; In 2009, the results of the Phase III clinical trial of the AIDS vaccine showed that the vaccine had a protective efficiency of 31%. This was the first time that scientists found detectable protective effects in a clinical trial; in 2016, the HVTN702 AIDS vaccine Effectiveness clinical trials were launched in South Africa, but at the beginning of 2020, the trial ended in failure.

  "There are many types of AIDS vaccines, including inactivated vaccines, live attenuated vaccines, protein subunit vaccines, synthetic peptide vaccines, DNA vaccines, carrier vaccines, etc." Dong Li introduced that due to the special nature of HIV, there are still a large number of inactivated vaccines. The security issue is not resolved.

For example, HIV that is not completely inactivated may cause latent infection, and the possibility that the viral nucleic acid that has not been destroyed after inactivation integrates into the chromosomes of human cells cannot be ruled out. Therefore, no inactivated AIDS vaccine has entered the clinical trial stage.

  "Because of the extremely high variability of HIV, the direction of the attenuated virus in the live attenuated vaccine cannot be predicted in vivo. There is a risk that the retrovirus will integrate into the host DNA and be reversed to wild-type. At present, HIV The possibility of successful development of traditional attenuated live vaccines is low." Dong Li said.

  Why is the AIDS vaccine so "dystocia"?

"This is because HIV mutates too fast." Fu Gengfeng explained that HIV will mutate randomly in each generation of human replication.

Vaccines or drugs need to target the corresponding sites to work, and the virus continues to mutate, which will cause drug resistance and make the vaccine or drug malfunction.

  The lack of ideal animal models is another important reason hindering the development of vaccines.

Fu Gengfeng said that pre-clinical animal model evaluation is an important part of vaccine research.

"HIV only infects humans, does not infect animals, and cannot replicate in animals. Therefore, preclinical in vitro tests of the AIDS vaccine cannot be carried out, and it is difficult to verify the safety and effectiveness of the vaccine."

  Fu Gengfeng introduced that Simian Immunodeficiency Virus (SIV) is very similar to HIV in terms of infection, transmission and incubation period. Researchers have successfully established a chimeric virus (SHIV) infection model of non-human primates.

However, SHIV infection method, dose and time parameters can significantly affect the results of vaccine evaluation.

  "In addition, how HIV escapes the surveillance of the human immune system is still unclear. This also poses challenges for vaccine development," Fu Gengfeng said.

  Antibody therapy has been used in clinical treatment trials

  In the process of "fighting wits and courage" with AIDS, humans have discovered a special "guard" against HIV-broad-spectrum neutralizing antibodies.

It can identify areas on the surface of HIV strains that are not prone to change, so that it has the ability to capture multiple strains, inhibit virus replication in patients, and effectively reduce HIV levels in humans.

  "Broad-spectrum neutralizing antibodies are mainly isolated and purified from the blood of infected persons. They can directly neutralize HIV strains and prevent the virus from invading immune cells. It can also stimulate other immune cells in the body after neutralizing the virus to jointly destroy the virus or Cells infected by viruses." Wu Jie, a professor at the School of Life Sciences and Technology of China Pharmaceutical University, told Science and Technology Daily that antiretroviral drugs inhibit and interfere with HIV entering human infected cells, while broad-spectrum neutralizing antibodies are The virus is blocked before it infects the cell.

  But this kind of weapon that kills HIV is very difficult to produce in the body of AIDS-infected people. Fu Gengfeng said, "Only 10%-15% of people can produce neutralizing antibodies after being infected with HIV, and only 2%-5% of patients have a broad spectrum. And antibodies. These broad-spectrum neutralizing antibodies generally appear in patients 2-3 years after being infected with the virus, and can neutralize most HIV strains at very low concentrations. These people have very low viral loads and do not develop disease. For the'elite' controller." Fu Gengfeng said.

  Studies have shown that the production of broad-spectrum neutralizing antibodies may be related to factors such as viral load, virus diversity, infection time, and host immune status.

  "At present, human research on broad-spectrum neutralizing antibodies still takes time. For example, the mechanism of its production is not fully understood. Some clinical trials are trying to induce broad-spectrum neutralizing antibodies in humans to make vaccines. But now Not yet successful." Tang Huamin said.

  What is gratifying is that in recent years, with the advancement and wide application of high-throughput neutralizing antibody screening and monoclonal antibody isolation technology, researchers have successfully isolated hundreds of broad-spectrum neutralizing antibodies from infected persons.

  On March 7, 2018, the FDA officially approved the first clinically applicable monoclonal antibody, which can bind to the main HIV receptor CD4 on the surface of T cells to prevent these cells from being invaded by viruses.

  Experts from the Chinese Center for Disease Control and Prevention of STDs and AIDS said that more and more antibodies have been used in clinical treatment trials.

  "In addition, scientists have also used reverse vaccinology technology to actively search for immunogens that can stimulate the body to produce protective HIV-specific antibodies, and try to use viral vector vaccines that carry genes that express antibodies to induce the human body to produce antibodies. It provides new ideas and new technologies for the research and development of AIDS vaccines." Wu Jie said.