Tuesday , March 2 2021

soon the end of the tunnel



Ambitious research for the development of the HIV vaccine began shortly after the discovery of the virus that François Barré-Sinoussi in 1983 led to the AIDS epidemic. The first effects of announcements soon followed. lack of effective treatment for the development of an emergency vaccine.

As early as 1984, US Secretary of State for Health Margaret Heckler said the vaccine would be available within two years. Vision shared by others – the virus has just been discovered and the complexity of his physiopathology was far from being regarded as its true extent. Moreover, the development of the seventies and eighties years of vaccines based on viral or bacterial proteins, and more not only on whole micro-organisms, strengthened this impulse of optimism.

But the efforts of researchers and doctors will face many difficulties for many years. To this point, 34 years later, the design of the prophylactic vaccine remains the priority of the HIV research. Today, however, the end of the tunnel looks closer than ever.

Lymphocytes, the main players in the immune system

With regard to pathogenic microorganisms, and especially viruses, our body has three lines of defense. The first is the barrier of skin and mucous membranes. If it is crossed, the attacker then faces innate immunity, which is based on cells capable of identifying foreign agents. They discover for these components present on their surface (sugars, proteins …), called antigens. This immunity is not specific to a particular agent, it attacks everything that is not the body. He also prepares the third line of defense, gained immunity. This is another that is stimulated by vaccination.

Acquired immunity is more subtle than innate immunity, and, most importantly, it is specific: its agents can recognize a particular microorganism and attack it. They also keep memory on previous encounters, which usually allows it to react faster in case of a new invasion of the same pathogen.

Acquired immunity is complex, but its essential actors are the class of white blood cells, lymphocytes. There are several types, among which are B (LB) and CD8 + T lymphocytes (LT CD8), whose role is predominant. The first antibody devices, molecules capable of specifically binding to the occupier to cover and neutralize it. Another role of the antibody is to draw attention to the immune system cells that will destroy the viruses thus processed. CD8 LT in the meantime directly destroys viruses infected with cells, thus preventing the spread of the infection.

The action of these two categories of lymphocytes coordinates the third type of lymphocytes, CD4 + LT lymphocytes (LT CD4), which stimulate them, and in some way play the role of conductors of the acquired immune response. These CD4 + T cells are the main target of HIV, which destroys them, which greatly complicates the establishment of an effective immune response.

How does the immune system work?

Train your body to defend itself

Immunization is an immune response that is a major maneuver in military training. Simulates the infection by the body believing the attacker has crossed his lines to trigger an immune response. In this way, when the body actually encounters the microbes, it will react faster.

The vaccines used may contain either fragments of microbes (i) against which protection is desired (protein vaccines), kill whole microbes (inactivated vaccines) or live, but weakened, without the virulent forms of these microbes (live vaccines). softened).

Live fire vaccines are those that cause the immunological protection closest to that resulting from a natural infection, resulting in the production of antibodies and the stimulation of CD8 LT. However, their use has a low risk of causing an infectious disease of the origin of the vaccine, in the case that the micro-organisms contain the recovery of their virulence. For obvious safety reasons, this type of vaccine can not be used in the case of HIV.

It was therefore necessary to resort to underground legs to obtain the same type of optimal immune response. But several obstacles stood in the way of the researchers.

HIV, an unusual virus

One of the major problems facing scientists working on the development of an HIV vaccine is the extreme variety of viruses. There are two main types of HIV viruses: HIV1 and HIV2, classified into different groups according to their origin (each group can be subdivided into subtypes).

HIV2 (divided into nine groups, A to I) is found mainly in West African patients, and in a very small proportion, in West Indians and India (in France, 1 in 2% of infections). HIV1, in turn, can be divided into four groups: M (principal, responsible for most HIV infections), O (except), N (non-M, non-O), P (last identified, 2009). ).

The HIV gene does not consist of DNA, but RNA. Like all RNA viruses, it makes many mistakes by multiplying itself. This stimulates many variants, slightly different. This leads to very important viral diversity not only between infected people but also within each one. Only one infected patient can carry millions of different variants, more than the differences created during the global flu epidemic! But this second requires the development of a new vaccine every year …

Another major problem in the development of the vaccine is that HIV infection does not necessarily generate protection. Indeed, antibodies produced after HIV infection do not protect enough. Moreover, CD8 LTs are able to control replication of the virus, but not to prevent infection. In the end, the "natural" immunity that can be obtained does not prevent the irritation of other HIV …

In the absence of treatment, HIV-infected patients will inevitably complete progression to the AIDS stage, with a significant exception of a small group of patients known as elite controllers. Others, which represent less than 1% of the population of infected people, have CD8 CD8 that can destroy infected CD4 LT and thus contain an infection.

The first milestones in the study of the vaccine

In 1987, the French team tested a live dried vaccine containing a modified vaccinia virus in order to become HIV1 protein. It was known that this technology, then recently, was allowed to induce antibody synthesis and to stimulate CD8 LT. Unfortunately, the tests were insufficient.

Almost all available vaccines against other infections rely on the induction of neutralizing antibodies that block the pathogen into the patient's cells. The first anti-HIV vaccine strategies therefore aim at the induction of such antibodies. However, in the case of HIV, these neutralizing antibodies are only effective against several types of viruses. They can not neutralize numerous variants present in the patient's body.

The first phase of 3 clinical trials (drug efficacy trials) of vaccines against HIV, which are expected to produce neutralizing antibodies, ran from 1998 to 2002. They identified AIDSVAX, involved more than 7,000 participants, in North America, the Netherlands and Thailand.

Inspired by the efficacy of a hepatitis B vaccine, based solely on proteins present on the wrapper of the virus, these HIV vaccines are protein vaccines that contain HIV protein envelopes (from two subtypes). HIV1 predominant in geographic areas where trials took place). But these tests failed to protect themselves from infection.

A year later, another phase of the 3 trial, RV144, began in Thailand. Conducted from 2003 to 2009 and involved more than 16,400 participants, it took the HIV protein used in AIDSVAX and combined with a harmless viral age, a canarypox virus that produces other HIV proteins.

For the first time, this approach has resulted in partial protection against HIV infection. Published in 2009, the results showed that the vaccine was protected by 31.2% of participants.

The most dangerous existing strategies

If the results of the RV144 research are encouraging, they have raised three questions:

  • they were based on just one trial and protected protection was short-lived;

  • protection was a priori directed only against the virus subtype;

  • this type of strategy has not caused a wide range of neutralizing antibodies that can block all types of existing HIV.

To find the answer to the first point, the HVTN702 test was set up in South Africa. This is based on the same strategy as the RV144 test, but vaccines are produced from the predominantly HIV-infected HIV in Africa and the study provides for additional injection of the vaccine one year after the initial injection to increase the duration of the immune response. Set in November 2017, its results are expected in January 2022.

In order to try to deal with other problems, the lack of diversity of protection, the researchers have developed "mosaic" vaccines. The vaccine strategy remains largely the same. Two different vaccines, viral vector and envelope proteins are used. However, the viral vector no longer produces the whole protein, which is derived from a single HIV virus, but parts of the protein from several strains. They identified researchers through bioinformatics so they could induce a wider immune response.

This strategy, confirmed in non-human primate models, has once again led to the establishment of an efficiency trial. Named HVTN 705 / HPX2008 "Imbokodo", it started in November 2018. It is expected to include 2,600 women in five countries in sub-Saharan Africa (mainly in South Africa) and will end in 2022.

Both strategies are likely to lead to a performance rate of around 50%. This may look poor, but a 50% effective vaccine would be a big step forward, not only at the individual level, but also at the level of the population. In fact, vaccinated populations would be people living in areas with high endemicity of the virus or risk (MSM, prostitutes …). The impact on the evolution of the epidemic of such a vaccine has been well modeled by the IAVI consortium (International Initiative for AIDS Vaccine).

Grayl neutralizing antibodies

These advances are more important, they do not allow the induction of a wide range of neutralizing antibodies. This is the only way to ensure highly efficient protection at the individual level.

If it has long been considered that such a vaccine will remain in the chicken, the latest data indicate that this is not the case. Studies in the United States, in groups of risky individuals, have shown that a wide range of neutral antibodies are detected in approximately 1% of people with HIV.

Despite the presence of these antibodies, the virus continues to be repeated in the patient's body. However, when these neutralizing antibodies are purified, it is observed that they are able to block the infection of more than 90 to 95% of the HIV sildene virus HIV in the laboratory.

This observation is important. Indeed, if, in the long run, a person infected with HIV must defend itself against many different viruses, he is initially infected with only one virus. If the vaccine can cause such neutralizing antibodies, this would be 90 to 95% protective!

Strategies for the induction of such antibodies are tested on animal tests. They are quite complex, and their clinical development in humans is much less advanced than those previously described.

Other anti-HIV vaccine strategies have been developed, including the induction of CD8 LT responses. Unfortunately, most of them have proved ineffective in clinical trials in humans.

For CD8 LTs, one runway is promising, but it is rated only for non-human primates, and encourages 50% protection.

The search for HIV vaccine is therefore still very active, and the results of two current Phase 3 clinical trials are highly anticipated. In addition, the recent discovery of the broad spectrum of neutralizing antibodies in some patients is a great hope for the future development of an effective vaccine at the individual level.

And regardless of the results achieved, knowledge gained through this work on HIV will improve the formation of vaccines against other complex pathogens that have a high mutation ability, such as a virus. flu.


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