Without a vaccine
Why there is still no HIV vaccination, who is to blame for this and how to live with it
Polina Loseva, N+1
We are waiting for a coronavirus vaccine in a matter of months, a year at most, and it seems that it is almost ready, it remains only to test it. However, it does not always happen so quickly. Scientists have been looking for the most elusive vaccine on the planet – from the human immunodeficiency virus – for almost forty years, and still have not found it. How did it happen? And what to do next: wait for it to appear, look for workarounds, or learn to live without it?
Premonitions
Until the middle of the XX century, a person could be vaccinated mainly against bacterial diseases – tuberculosis, tetanus, cholera: their pathogens are large, they are easy to consider and simply grow. Viruses have always been much more difficult to work with – especially considering that they do not reproduce outside of cells. The situation was turned around by the "fathers of modern vaccines" – John Enders, Frederick Robbins and Thomas Weller, who learned how to grow polio virus in cell culture.
After that, the "fathers" were awarded the Nobel Prize, and the industry rolled up its sleeves and took up the extermination of viruses: 1952 – the first working vaccine against polio, 1954 – Japanese encephalitis, 1957 – adenovirus infections, 1963 – measles, 1967 – mumps, 1970 – rubella.
A protocol has appeared to save humanity. Step one: isolate the virus. Step Two: grow it in culture. Step three: inactivate (neutralize) the enemy or select his weakened options. Step four: Check whether the resulting viral particles cause an immune response to animals. Step five: Test the effectiveness and safety in humans. A century and a half after Jenner's first experiments, the development of antiviral vaccines turned from creative work into technical work.
Jenner has spent decades on his work, his followers have learned to do it much faster. From the moment polio was "settled" in cell culture, about seven years passed before the official approval of the Salk vaccine. It took about nine months to produce the measles vaccine, rubella was dealt with in five, the mumps still holds the palm of the championship – four years from the isolation of the virus to the finished vaccine.
By the eighties of the XX century, many viruses remained elusive, but the first serious victories appeared. With the help of antiviral vaccines, it was possible not only to stop the polio epidemic in many countries, but also to completely eradicate smallpox. Perhaps it was these successes that allowed the Secretary of the US Department of Health, Margaret Heckler, to promise the press on April 23, 1984 that the new, newly discovered HTLV-III virus (a little later, the more well–known name HIV, or HIV, will be fixed for him) will be able to cope - that is, to make a vaccine – in just a couple of years.
In his book And the band played on, journalist Randy Shields recalls that the doctors who accompanied Heckler at the press conference literally turned white after these words– they had no idea where she got this figure from. However, they could hardly have guessed then how long this chase would actually last.
In the 36 years since Heckler's statement and 39 years since the beginning of HTLV-III research, much has changed in the world. Inactivated vaccines have gone out of fashion, losing their popularity to viral vectors, polio has remained only in a few countries, and the flu vaccine has learned to be updated every year. Epidemics of SARS and swine flu have begun and ended in the world, the SARS-CoV-2 pandemic has already claimed more than half a million lives, and the survivors hope for the imminent appearance of a vaccine.
Meanwhile, hundreds of thousands of people die from the consequences of HIV infection and tens of millions suffer a year, and the promise of the Heckler could not be fulfilled – not in two years, not in ten, not in thirty-nine.
The chase
Two years is the time in which you can have time to walk along a well–trodden path in advance. You can meet it if you already have a virus isolated, antibodies from the blood of people who have been ill, examples of working vaccines of the same type (this is what helped the developers of SARS-CoV-2 vaccines to start quickly) and a proven method of their production – and all this provided that the vaccine passes clinical trials (which last from several months to a year) from the first time. In other words, if you are well prepared at first, and then you are lucky.
At first it seemed that the HIV vaccine could also be "written off" from other, already successfully launched vaccines. And before the eyes of scientists there were two encouraging examples. I noticed one of them Donald Francis, one of those who stood at the origins of working with HIV, is a vaccine against feline leukemia virus. Like HIV, it belongs to retroviruses, and it was the only retrovirus that had been defeated by that time.
HIV envelope protein (Env) with marked targets for antibody attack (Dennis R Burton et al. / Nature Medicine. 2004).
Feline leukemia was treated with an inactivated vaccine, but it is dangerous to try this method on humans, especially if we are talking about a virus for which there is no cure – if something goes wrong, then there will be nothing to save the subjects. Therefore, it was decided to "write off" the technology from another instrument of victory – the hepatitis B vaccine. It appeared in 1981 – it was an antigen obtained by crushing viral particles from the blood plasma of people who had been ill. In 1986, the vaccine was improved: by that time the boom of recombinant DNA had begun, the hepatitis antigen had learned to grow in yeast cells, and it seemed that HIV could be defeated in the same way.
Two years after Heckler's promise, the first vaccines based on viral antigens, indeed, have already been tested on animals. But people were the first to receive another vaccine – based on the Vaccinia virus with an embedded section of the HIV genome. Clinical trials in 1986 were conducted on citizens of Zaire and, as often happens in such cases, were ethically controversial: it turned out that children participated in them. In addition, as it turned out later, some of them died from the side effects of the vaccine, and after that no one tried to evaluate the safety and effectiveness of the trial vaccine. Since then, more than two hundred clinical trials of various vaccines have already passed in the world, but less than a dozen have reached the third phase. The rest could not force the human immune system to respond to the invasion and take timely measures.
It took only 8 years before it became clear what was wrong with the first generations of vaccines. All the antibodies produced by the body of the subjects worked only with model, laboratory strains – and were powerless against the real, "wild" virus. Then, for the first time, scientists thought (although they had known about it since 1985) that the army of their enemies was heterogeneous. For example, it turned out that different types of HIV use different "doors" inside the cells. Those that served as the laboratory standard got into lymphocytes through the CXCR4 molecule, but in the blood of real patients there were also those that entered through the CCR5 receptor.
However, it later turned out that the type of "door" that the virus uses is not related to its vulnerability to antibodies. Then another assumption appeared: perhaps the virus simply has many faces, and we are not talking about one type of it, but about the whole family. Indeed, since 2000, scientists have identified more than a dozen types of HIV (from A to L) and continue to find new subtypes. But they also could not be unambiguously linked to immunogenicity: in other words, the virus belonging to one type or another is not related to how it will react to antibodies.
Phylogenetic tree of human immunodeficiency viruses of group M, the color indicates a recently discovered representative of the subtype L (Yamaguchi, Julie et al. / JAIDS, 2020).
Apparently, the trouble with the human immunodeficiency virus is not in the diversity of its types, but in the fact that this diversity grows within each individual organism. After HIV colonizes human cells, it continues to mutate, and does so faster than the body has time to develop antibodies against the previous "version" of the enemy. According to the latest calculations, in one round of copying in a cell, it accumulates an average of 0.004 mutations per base pair, that is, only about 36. This is at least an order of magnitude more common than that of the hepatitis virus.
Strictly speaking, this is the fastest mutating biological object known to us. Thus, it turns out that we have to teach the immune system to produce antibodies to a multi-faceted enemy, which, in addition, changes shoes on the run. Roughly speaking, if the creation of other vaccines is skeet shooting, then in the case of HIV, this skeet flies faster than sound.
The situation is complicated by the fact that after the first miss, the gun can be thrown away. Since HIV is a retrovirus, it embeds its genes into nuclear DNA. And we can't erase them from there anymore –at least, we haven't learned yet. This means that if the vaccine did not defeat the enemy with the first blow, then, once inside the cells, he will not leave from there. You can suspend its reproduction, you can forbid it to go outside (which is what modern antiretroviral drugs are doing), but in any case it will remain inside. You'll have to live with him.
As a matter of fact, that's why we don't have natural success stories either. There are still no known cases in which a person would have had HIV infection in the classical sense of the word, that is, he first carried the virus in himself, and then stopped, without any outside intervention. And this is a unique problem in its own way. Usually, when scientists start looking for a vaccine, they have a real example of what their victory should look like – that is, a person who was sick and cured – it is his victory that they are trying to reproduce. Knowing the answer in advance, they are looking for a way to come to it.
But this time it's completely different. Anthony Fauci, who headed the National Institute of Allergy and Infectious Diseases of the USA (NIAID) in 1984, warned from the very beginning: there is no answer, and we don't even know if this problem is solved in principle. No one can know in advance whether we will be able to cope with it better than nature.
Acceptance
36 years have passed. On July 1, 2020, Fauci published another program text on the difficulties and prospects of combating HIV. Now he is more optimistic than in 1984: the permanent director of NIAID writes about "technological advances that brought hope to a once desperate situation" and calls victory over the epidemic "conceivable".
Does this mean that people have become less ill? Alas, no. The number of infected continues to grow inexorably, even if it does so more slowly than before the 2000s (Russia, alas, is one of the few exceptions to this trend.
Maybe we finally have a vaccine? Not either. The best result we have today was obtained back in 2009 – then, during tests in Thailand, 31 percent fewer people were infected with the virus in the group of people who received the vaccine than in the control group. Two other clinical trials are in full swing, in Africa (phase 2b) and in the USA (phase 3). Both use mosaic vaccines that contain fragments of proteins from different types of HIV. Both are far from over.
But if some vaccine breaks through the trials, it will not necessarily be the end of the epidemic. With such a multifaceted opponent as HIV, there are no half measures. If at least in a small percentage of cases the vaccine misfires (which is generally typical for vaccines), then rare unprotected organisms will turn into incubators where HIV can quickly evolve into a new subtype unfamiliar to us. And collective immunity, which has made it possible to cope with epidemics of other viruses, simply will not be able to form. Therefore, even if a vaccine appears, we will probably have to live as if it does not exist.
Fauci's optimism is based not so much on scientific progress, but on the fact that the world is gradually learning to coexist with HIV infection, just as the body of patients gradually gets used to living with the virus inside. Having no chance to leave the virus behind, we can still run side by side with it and try to get ahead of it by at least half a step.
We have learned how to do this inside the body of most HIV-infected people: modern medicines allow them to match the life expectancy of those who are lucky enough to live it without the virus. None of the drugs allows you to get rid of HIV forever (although recent developments may allow you to take medications twice a year, not every day), but they help break the chain of infections: in the blood of most people taking antiretroviral therapy, the virus is not detected, which means they do not transmit it to others. This principle is called "treatment as prevention": in the absence of a vaccine, it had to be replaced with medicine.
Another way to overtake the virus is prevention. If a small concentration of antiviral agents is constantly maintained in the blood, then HIV does not have time to penetrate the cells and multiply in them. Protection against infection during prevention reaches 99 percent – but you will have to drink pills every day, we still cannot protect ourselves once and for all.
The strategy of running ahead is gradually bearing fruit. Although the number of new HIV cases continues to be measured in millions every year, deaths from the effects of infection have halved over the past 15 years. By 2020, the UN has set itself the task of "90-90-90": 90 percent of infected people should receive their diagnosis, 90 percent of people with a diagnosis should receive therapy, 90 percent of people on therapy should live without detectable virus in their blood. The deadline is coming to an end, and while we are waiting for the results, it is difficult to say how far this plan has been implemented. But you can notice that there is not a word about the vaccine in it.
Even in the last program text of Fauci, the vaccine is mentioned only in passing – as the final touch, without which it will not be possible to talk about a complete victory over the epidemic. But she will not be the weapon and she is not the main goal for HIV fighters – because she is probably unattainable.
Against this background, the SARS-CoV-2 virus does not seem to be such a dangerous enemy - at least from what we know about it today. It is not as diverse and mutates more slowly. Many people recover from illness and become immune to the virus – which means we have something to focus on. We even have the best practices of vaccines against his relatives and predecessors.
So the task looks easy to solve – and if something goes wrong, we know ways to negotiate with the epidemic and without a vaccine.
It just takes a lot longer.
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