Why hasn't there been an AIDS vaccine yet?

Author: Sun Caijun (School of Public Health, Sun Yat-sen University (Shenzhen)/Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences)

The article comes from the Science Academy official account (ID: kexuedayuan)

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The situation of AIDS prevention and control is grim, which is a fact known to everyone. However, what is puzzling is that AIDS is a typical infectious disease caused by viruses, and vaccines are the greatest invention of mankind to fight against viruses. Through vaccines, people have eradicated smallpox and effectively controlled the spread of polio, hepatitis B and other infectious diseases. Why has there been no effective vaccine for AIDS, which is so widely spread?

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HIV is a small virus, but a huge threat

AIDS is the abbreviation of "Acquired Immune Deficiency Syndrome", which comes from the English abbreviation AIDS (Acquired Immune Deficiency Syndrome). It is a chronic, progressive and fatal disease caused by infection with the Human Immunodeficiency Virus (HIV). In the early 1980s, people discovered AIDS. At that time, it was a veritable terminal illness. Almost all patients with similar symptoms quickly died of opportunistic infections and systemic organ failure caused by the virus.

The HIV virus is mainly transmitted to the human body through three ways: sexual behavior (homosexual and heterosexual), blood (such as a history of unclean injections, unclean surgery, unclean blood transfusions or blood donations, etc.), and mother-to-child transmission.

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From a purely biological perspective, this virus is very "small", with a genome of only 10kb and can only encode 9 genes, but the harm it causes is very "big". The latest data from the World Health Organization (WHO) and the Joint United Nations AIDS Program show that there are still 36.9 million HIV-infected survivors in the world, and about 35.4 million patients have died of AIDS. In other words, the HIV virus has infected at least 70 million people on the earth, which is more than the death toll in World War II. And the number of infected people is still increasing at a rate of about 2 million per year (1.8 million in 2017).

The AIDS epidemic in my country is also very serious. Data from the 5th National AIDS Academic Conference held in Kunming in 2018 showed that there are at least 820,000 surviving AIDS patients in my country, and the rapid growth trend has not been curbed. For example, 135,000 new infections were found in 2017 alone. What is more worrying is that the AIDS epidemic in my country has shifted from high-risk local groups such as drug users and blood sellers to sexual transmission among the general population, and more than 95% of new infections are infected through homosexual or heterosexual sex.

Why is it so difficult to develop an AIDS vaccine?

Through vaccines, humans have eradicated smallpox and effectively controlled the spread of many infectious diseases, including polio and hepatitis B. Preventing infectious diseases through vaccination is one of the greatest public health achievements made by humans in the 20th century. "The significant impact of vaccination in reducing human mortality and promoting population growth cannot be matched by antibiotics."

However, humans do not yet have an effective vaccine against HIV.

AIDS was first discovered and reported in 1981, and the AIDS virus was soon isolated in 1983. People were optimistic that since the pathogen was found so quickly, they could quickly develop an AIDS vaccine by imitating the experience of developing other virus vaccines.

As early as 1984, the U.S. Surgeon General announced that an AIDS vaccine would be available in two years. More than a decade later, in 1997, U.S. President Clinton confidently announced the "Manhattan Project for AIDS vaccines," which was as important as the "Manhattan Project for the atomic bomb" announced by President Roosevelt in 1939 and the "Manhattan Project for manned lunar landings" announced by President Kennedy in 1961. "36 years ago, President Kennedy set the goal of reaching the moon, and we accomplished it ahead of schedule. Today, in the age of biology, let us set a new national scientific goal: let us devote the next decade to the development of an AIDS vaccine."

However, after the "Manhattan Project for the atomic bomb" and the "Manhattan Project for manned moon landing" were successfully completed after 6 and 8 years respectively, more than 20 years after the announcement of the "Manhattan Project for AIDS vaccine", AIDS vaccine is still a dream and the AIDS epidemic is still raging around the world.

Developing an effective AIDS vaccine has become one of the most challenging scientific problems, and countless scientists have and are struggling for it all their lives. Although the development of AIDS vaccines has begun since the 1980s, the record of human beings and AIDS virus is 0:200! Yes, AIDS virus has won more than 200 times, and there is still no successful vaccine.

There are many reasons why the development of AIDS vaccines is so difficult, mainly including:

1. HIV is highly variable, and it is hard to find its trace, just like it can change into 72 different forms. Traditional vaccine research methods are ineffective in combating HIV.

2. HIV can be integrated into the genome of host cells like a dog-skin plaster, so it cannot be removed unless the cells are killed. This brings great trouble to both treatment and vaccine development.

3. The HIV virus can only infect humans and cannot infect other species and cause disease (a few species of orangutans can be infected but do not become ill). Therefore, there is a lack of good animal models in the research of HIV vaccines.

4. Commercial factors. Current AIDS drug therapy requires patients to take medication for life, which brings huge profits to many pharmaceutical companies. Therefore, they do not want to (shh, it should be said in public that they do not have much interest in) invest in AIDS vaccine research and development.

Modified from: Cohen. Science. 2017. Promising AIDS Vaccine's Failure Leaves Field Reeling

The “three major battles” in developing an AIDS vaccine

Looking back at the history of AIDS vaccine development, it can be said that the search for an effective vaccine is like shooting at nothing or looking for a needle in a haystack. It is a journey full of twists and turns. Throughout the more than 200 battles, large and small, although humans have always been in a passive state of being beaten, they have not given up.

The research of AIDS vaccines can be divided into three stages: vaccines that induce humoral immunity; vaccines that induce T cell immunity; vaccines that induce both antibody and cellular immunity. We can compare these stages to the three major battles launched by humans against the AIDS virus. After experiencing these three major battles, although humans have not yet been liberated from the evil AIDS disease, they have found the direction to continue to move forward and fight, and see the dawn of victory.

First Battle Phase

The purpose of this campaign is to induce neutralizing antibodies against HIV based on the classic vaccine strategy. The AIDS vaccine research that started in 1984 focused on inducing antibodies to prevent viral infection as the main goal, without considering the role of cellular immunity. In 2003, two AIDS vaccine phase III clinical trials ended in Europe, the United States and Thailand, which were the clinical verification of the research results of the first stage of AIDS vaccine development in a practical sense. The results showed that vaccines that simply induce antibody production do not have a real protective effect. This campaign is not over yet, and many scientists are still committed to developing new immune strategies to induce broad-spectrum neutralizing antibodies.

Second Battle Phase

After many failed experiments in inducing antibody strategies, humans began to reflect on the research and development direction of AIDS vaccine strategies and turned most of their efforts to another direction, which is to emphasize that vaccines can induce efficient cellular immune responses.

This stage of the campaign mainly uses recombinant viral vector vaccines that induce cellular immune responses (vaccinia, adenovirus, canarypox virus, etc.), because in theory cellular immune responses can effectively control viral replication and infection, and mathematical models also show that reducing the viral load by 1 log value can effectively reduce the transmission rate in the population, which allows clinical trials to see the application prospects of this vaccine.

One of the most notable achievements was the AIDS vaccine developed by Merck using human adenovirus type 5 as a vector. However, according to the clinical trial results published in September 2007, simply emphasizing cellular immune response could not produce a protective effect. The failure of this T cell response vaccine undoubtedly dealt a severe blow to the vaccine research and development field. People once questioned whether an effective AIDS vaccine could be developed, and the entire field was filled with despair.

The third battle stage

After countless failures, scientists still did not give up. After a short period of rest, they launched another attack on the HIV virus. Currently, scientists generally believe that an effective HIV vaccine needs to induce a balanced humoral and cellular immune response at the same time.

During viral infection, neutralizing antibodies can neutralize some viruses as the first line of defense, which buys time for the subsequent cell-mediated memory response to activate. A strong cellular immune response clears virus-infected cells and reduces the viral load, thereby reducing the transmission rate of HIV in the population. Therefore, this stage focuses on the balance of humoral and cellular immune responses, and DNA vaccines, live vector vaccines, and multivalent protein vaccines are fully developed. Combined immunization of various vaccines (prime/boost strategy) has become the mainstream direction of AIDS vaccine development.

The new combined vaccine (RV144) developed by the US military and Thailand, announced in September 2009, can reduce the risk of human infection with HIV by 31.2%. This is the first time in human history that the feasibility of developing an effective AIDS vaccine has been proven in humans. This experiment gives us hope for the development of an effective AIDS vaccine. In order to find the ultimate effective AIDS vaccine, researchers including my team are trying to use a variety of different types of vaccines in combination in order to find the best combination.

The data come from the IAVI clinical trial database.

Conclusion

In the journey of conquering this unprecedented enemy of the century - AIDS, countless scientists have been, are and will continue to fight for it throughout their lives.

Highly effective antiretroviral therapy (i.e., "cocktail therapy") can effectively control the progression of AIDS, allowing infected people to live with dignity "like normal people", but this therapy only temporarily "controls" the virus, and it is unable to completely eliminate the virus in the body. As long as the medication is stopped, the suppressed HIV virus will be like a monkey under the Five Finger Mountain whose "seal and curse" are removed, and it will use its own wild power to rebound. Therefore, once infected, AIDS patients must take medication for life.

In order to completely control and eliminate the AIDS epidemic, prevention is the best way. Prevention includes behavioral intervention and vaccination. Behavioral intervention includes increasing the intensity of health education and publicity; promoting methadone substitution therapy and clean needles for drug addicts; avoiding risky sexual behaviors, promoting safe sex knowledge, and keeping oneself clean; and seeking medical treatment as soon as possible once infection is discovered. Before the successful development of an effective AIDS vaccine, behavioral intervention is an effective and necessary means of preventing AIDS.

The ultimate goal of human beings to prevent HIV infection more scientifically and effectively should be an effective AIDS vaccine. In the long journey of developing AIDS vaccines, scientists have been working hard and never give up. The author's research team has long focused on the research of new strategies for AIDS prevention and treatment, and has carried out a number of innovative work in vaccine design, immunotherapy, infection mechanisms, etc., and explored a series of new AIDS vaccine strategies. How many years will humans have to wait for a successful AIDS vaccine? It is not possible to give a definite numerical answer now, but we are always on the road to conquer it...

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