Are we finally getting closer to an HIV vaccine?

Since the mid-1980s, when HIV was discovered and the causal link with AIDS was demonstrated, research to develop a vaccine has never stopped. But despite the commitment of the scientific community and a huge amount of uninterrupted funding, there have only been failures (with one, partial exception): now, however, the discovery that a fraction of infected individuals produce broad-spectrum neutralizing antibodies has led to the development of new experimental vaccines, currently in clinical trials, with innovative strategies such as Germline Targeting.

In his recently published autobiographical book, On Call. A Doctor’s Journey in Public Health, Anthony S. Fauci, head of the National Institute for Allergy and Infectious Diseases in Bethesda, USA for 38 years, declares himself skeptical about the possibility of discovering a vaccine to prevent HIV infection, the cause of acquired immunodeficiency syndrome (AIDS), 95% lethal in the absence of therapy. However, the need for an HIV vaccine, especially in poorer countries with poor access to combination antiretroviral therapy (cART), remains intact.

After a period characterized only by the failures of the latest phase III clinical trials, a “package” of publications published almost simultaneously in the main scientific journals puts the possibility of achieving this Holy Grail of vaccination back into play. But let’s rewind the tape before getting into the merits.

After the discovery of the virus in 1983 by scientists at the Pasteur Institute in Paris, awarded the Nobel Prize in Medicine or Physiology in 2008, and the demonstration of the causal link with AIDS in 1984 (thanks to the US team led by Robert C. Gallo, not included in the Prize), the search for a vaccine immediately began: its discovery was expected “in a couple of years”, as Margaret Heckler, secretary of the US Department of Health and Human Services, declared. Never was a prediction more wrong! Despite the commitment of the scientific community and a huge amount of uninterrupted funding, the history of vaccine research has only collected failures, with one partial exception: the RV144 study conducted in Thailand, which demonstrated a protection of about 30% of vaccinated people compared to controls in the first 3 years of infection, as already discussed on Scienza in rete. Unfortunately, the result was not confirmed by subsequent clinical studies which, however, modified many parameters compared to RV144, collecting only failures.

But why has it not yet been possible, with the partial exception mentioned above, to obtain a vaccine even only partially effective? Let’s summarize, briefly, the main reasons:

There is no spontaneous elimination of the virus from an infected person. Our immune system therefore lacks “the code” for eliminating the retrovirus, because it integrates into the genome of T lymphocytes and macrophages, ensuring its “lifelong” persistence;

The virus is characterized by very high spontaneous variability. Its key enzyme, reverse transcriptase (which copies the viral RNA genome into a DNA version that can integrate into the genome of the infected cell) does not have the “proofreading” function present in many viruses, including the SARS and COVID-19 coronaviruses;
Neutralizing antibodies (nAb) that can prevent infection are generated only several months after infection. The first antibody response is in fact directed against the sugar shield that protects the glycoprotein gp120 Env (the “key” used by the virus to bind to the primary entry receptor, the CD4 molecule, and the chemokine co-receptor CCR5 or CXCR4), while specific T lymphocytes are able to control the quantity of infected cells, but not to eliminate them completely (mainly because some infected cells harbor the integrated and latent virus, therefore “invisible” to immune recognition). Incidentally, in the case of the RV144 study, the (partially) protective immune response was not conventional, but associated with the secretion of non-neutralizing antibodies.

In this discouraging scenario, however, a light has come on. Scientific research is a continuum, so it is often very difficult to define when a new phase begins in a given research area. In the long history of the search for an anti-HIV vaccine, a scientific turning point, at the basis of the studies in question, was having demonstrated that a not small fraction (about 10%) of infected individuals produce, albeit belatedly, broad-spectrum neutralizing antibodies (broadly neutralizing Ab, bnAbs) often endowed with extraordinary efficacy; in fact, some are now used as complementary or alternative drugs to classic antiretroviral drugs…