soon the end of the tunnel

Ambitious research to develop an HIV vaccine began soon after the discovery of the virus that led to the AIDS epidemic by Françoise Barré-Sinoussi in 1983. The first announcement effects soon followed. lack of effective treatment making the development of an urgent vaccine.

As early as 1984, United States Secretary of State for Health Margaret Heckler declared that a vaccine would be available within two years. A vision shared by others – the virus had just been discovered and the complexity of its physiopathology was then far from being considered to its true extent. In addition, the development in the 1970s and 1980s of vaccines based on viral or bacterial proteins, and no longer solely on whole micro-organisms, reinforced this momentum of optimism.

But the efforts of researchers and doctors would face many difficulties for many years. To the point that, 34 years later, the development of a prophylactic vaccine remains a priority of HIV research. Today, however, the end of the tunnel seems closer than ever.

Lymphocytes, major players in immunity

In the face of pathogenic microorganisms, and especially viruses, our body has three lines of defense. The first is the barrier of the skin and mucous membranes. If it is crossed, the invader then faces the innate immunity, which is based on cells capable of recognizing foreign agents. They detect for that 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. It also prepares the third line of defense, acquired immunity. It is the latter that is stimulated by vaccination.

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

Acquired immunity is complex, but its essential actors are a particular clbad of white blood cells, the lymphocytes. There are several types, but B-lymphocytes (LB) and CD8 + T-lymphocytes (LT CD8) play an important role. The former make antibodies, molecules that can bind specifically to an invader to cover and neutralize it. Another role of antibodies is to attract the attention of the cells of the immune system that will destroy the viruses thus covered. The CD8 LTs, meanwhile, directly destroy the cells infected by the viruses, thus preventing the spread of the infection.

The action of these two categories of lymphocytes is coordinated by a third kind of lymphocytes, the CD4 + LT lymphocytes (LT CD4), which stimulate them, playing in a certain way 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 setting up of an effective immune response.

Train the body to defend itself

Immunization is the immune response that the great maneuvers are in military training. It simulates an infection by making the body believe that an invader has crossed its lines, in order to trigger its immune response. In this way, when the body actually encounters the microbe concerned, it will react more quickly.

The vaccines used may contain either fragments of the microbe (s) against which protection is desired (protein vaccines), killed whole microbes (inactivated vaccines), or live but attenuated, non-virulent forms of these microbes (live vaccines). attenuated).

Live attenuated vaccines are those that induce the immune protection closest to that resulting from natural infection, resulting in both antibody production and stimulation of CD8 LT. However, their use has a low risk of inducing an infectious disease of vaccine origin, in the case where the microorganisms they contain recover their virulence. For obvious safety reasons, this type of vaccine could not be used in the case of HIV.

It was therefore necessary to resort to subterfuges in order to obtain the same type of optimal immune response. But several obstacles stood on the road of the researchers.

HIV, an elusive virus

One of the main problems faced by scientists working on the development of an HIV vaccine is the extreme diversity of the virus. There are two main types of HIV virus: HIV1 and HIV2, clbadified into different groups according to their origin (each group can be subdivided into subtypes again).

HIV2 (divided into nine groups, from A to I) is found mainly in patients from West Africa, and in a very minor way, in the inhabitants of western countries and India (in France it represents 1 at 2% of infections). HIV1, for its part, can be subdivided into four groups: M (Major, responsible for the majority of HIV infections1), O (Outlier), N (non-M, non-O), P (last identified, in 2009). ).

The HIV genome does not consist of DNA, but RNA. Like all RNA viruses, it makes a lot of mistakes by multiplying itself. It gives rise to many variants, slightly different from each other. This leads to a very important viral diversity not only between the infected persons, but also within each of them. Only one infected patient can carry millions of different variants, more than the diversity generated during a global influenza outbreak! But the latter requires the development of a new vaccine each year …

The second major problem in developing a vaccine is that HIV infection does not necessarily generate protection. Indeed, antibodies produced after HIV infection are not sufficiently protective. In addition, CD8 LTs are able to control the replication of the virus, but not to suppress the infection. Finally, the "natural" immunity that could be obtained does not prevent superinfections by other strains of HIV …

In the absence of treatment, HIV-infected patients will inevitably end up progressing to the AIDS stage, with the notable exception of a particular small group of patients known as elite controllers. The latter, which represent less than 1% of the population of infected persons, possess CD8 CD8 capable of destroying the infected CD4 LT, and thus contain the infection.

The first milestones of vaccine research

In 1987, a French team tested a live attenuated vaccine containing a modified vaccinia virus to make it an HIV1 protein. It was known that this technology, then recent, allowed to induce the synthesis of antibodies and to stimulate CD8 LT. Unfortunately the tests were inconclusive.

Virtually all available vaccines against other infections based on the induction of antibodies, which block the penetration of the pathogen into the patient's cells. The first anti-HIV vaccine strategies targeted the induction of such neutralizing antibodies. However, in the case of HIV, these antibodies are only effective against a few strains of the virus. They can not neutralize the plethora of variants present in the body of a patient.

The first phase 3 clinical trials (trials to evaluate the efficacy of a drug) of HIV vaccines expected to produce neutralizing antibodies took place from 1998 to 2002. Called AIDSVAX, they involved more than 7,000 participants, in North America, the Netherlands and Thailand.

Inspired by the effectiveness of the hepatitis B vaccine, based only on the proteins present on the virus envelope, these HIV vaccines were protein vaccines containing HIV envelope protein (from two subtypes). HIV1 prevalent in the geographic areas where the trials were conducted). But these tests failed to protect against infection.

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

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

The most promising current strategies

If the results of the RV144 trial were encouraging, they raised three issues:

• they were based on only one trial and the protection conferred was short-lived;

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

• this type of strategy did not induce broad-spectrum neutralizing antibodies capable of blocking all types of existing HIV.

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

To try to address the lack of diversity in protection, researchers have developed "mosaic" vaccines. The vaccine strategy remains largely the same using two different vaccines a viral vector and envelope proteins. However, the viral vector no longer produces an entire protein derived from a single strain of HIV, but pieces of protein from several strains. These have been identified by researchers through bioinformatics as being able to induce a broader immune response.

This validated strategy in nonhuman primate models has again led to the establishment of an efficacy trial. Dubbed 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 South Africa), and end in 2022.

Both strategies are likely to lead to success rates of around 50%. This may seem weak but having a 50% effective vaccine would be a big step forward both at the individual level but also at the population level. In fact, the vaccinated populations would then be those living in areas of high endemicity of the virus or at risk (MSM, prostitutes …). The impact on the evolution of the epidemic of such a vaccine has been very well modeled notably by the IAVI consortium (International AIDS Vaccine Initiative).

The grail of neutralizing antibodies

Important are these advances, they do not allow to induce neutralizing antibodies broad spectrum. This is the only way to ensure highly effective protection at the individual level.

If it has long been thought that such a vaccine would remain a chimera, recent data suggest that this is not the case. Studies in the United States in at-risk cohorts have found that broad spectrum neutralizing antibodies can be detected in approximately 1% of HIV-infected individuals.

Despite their presence, the virus continues to replicate in the body of these patients. However, when these antibodies are purified, it is noted that they are able to block the infection of more than 90 to 95% of HIV1 strains in the laboratory.

This is important because if, in the long term, an individual infected with HIV has to defend against many different viruses, he is initially infected with a single virus. If a vaccine could induce such antibodies, it would be 90 to 95% protective!

Strategies are currently underway in animal trials to induce such antibodies. 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 based notably on the induction of a CD8 LT response. Unfortunately, most of them have proved ineffective in clinical trials in humans.

With respect to CD8 LTs, only one track appears promising, but it has been evaluated only in non-human primates, inducing a 50% protection.

The search for an HIV vaccine is still very active, and the results of the two ongoing Phase 3 clinical trials are highly anticipated.

The recent discovery of the existence of broad-spectrum neutralizing antibodies in some patients represents great hope for the future development of an effective vaccine at the individual level.

And regardless of the results, the knowledge gained from this HIV work will improve the design of vaccines against other complex pathogens that have a high ability to mutate, such as the virus. of the flu.