One step further towards an HIV vaccine: and this one performed as expected

A recent experimental HIV vaccine protected 50% of a group of twelve rhesus monkeys from infection by Simian Immunodeficiency Virus (SIV). Furthermore, it did so by providing so-called ‘sterilising immunity’, meaning that it completely prevented infection in these monkeys rather than offering the more limited goal of ‘functional immunity’, where infection still happens but is harmless.

In addition, two monkeys that were infected did appear to develop functional immunity: although experiments showed their cells still harboured HIV DNA, they became ‘elite controllers’, maintaining an undetectable viral load in blood. Taken together, then, this vaccine provided significant protection against SIV to two-thirds of the monkeys vaccinated.

The vaccine

The vaccine, which recently garnered widespread media attention, is an improvement on the previous vaccine developed by the team which Aidsmap reported on in 2012. Although at the time of reporting, six out of twelve monkeys given that vaccine had not become infected, ultimately only three remained uninfected, as seen in this later paper, though three more became elite controllers.

This vaccine uses what is a now-familiar ‘prime/boost’ strategy by using one component to kickstart immune responses to HIV then another to amplify them. The 'prime’ consists of a viral vector – this is the shell of a virus that is unrelated to HIV but which contains snippets of HIV genes. The idea of using a vector is that it can ‘infect’ cells precisely as the actual virus would and more efficiently deposit its HIV antigens (immune stimulants) inside them. However in this vaccine neither the vector not the HIV genes can cause an ongoing, proliferative viral infection.

In this case the viral vector was Ad26, one of a family of common-cold viruses, but not one that commonly infects humans (so few would be immune to the viral vector). It contained bits of the env, gag and pol genes from a SIV virus. This prime vaccine was given in two doses, one six months after the first.

This was followed up by a boost of three doses of the p140 envelope protein (the ‘knobs’ on the surface of SIV/HV) from a different variety of SIV, given 12, 13 and 14 months after the first prime dose. This was not inside a viral vector, but was given inside an ‘adjuvant’ or chemical amplifier consisting of liposomes, tiny lab-made ‘fat bubbles’ containing the protein, which are designed to penetrate cell membranes better. This vaccine was called the ‘ad/env’ vaccine by the researchers.

Twelve monkeys were given this ad/env vaccine. In addition, another twelve were given an alternative ‘ad/ad’ vaccine where the second vaccine as not the amplified gp140 protein, but a second vector vaccine based on a different variety of adenovirus, Ad35.

A third group of eight monkeys were given a ‘sham’ or placebo vaccine of normal saline.

Two years after the initial prime vaccine dose and ten months after the last boost, all 32 monkeys were then challenged with repeated, huge, rectally-introduced doses (500 times the dose that infects 50% of susceptible cells in a lab dish) of an SIV virus called SIVmac251. This was chosen because it is not a variety that is easily susceptible to ‘neutralisation’ by antibodies and thus sets a high challenge to a candidate vaccine. Six challenge doses were given altogether, a week apart.

To confirm these findings, and to perform an experiment more closely related to human HIV, a second group of 20 monkeys also received two injections of a adenovirus vector prime, but one containing human HIV DNA rather than monkey SIV DNA.They also received an adjuvanted envelope protein, but this time from a human clade C HIV virus. Furthermore, these boosts were delayed by a year compared with the SIV protein boosts, and given in five doses, so they received the first dose three years after their first prime dose and the last 3 years and six months after it.

Another eight monkeys received the same number of doses, but of the adjuvanted human env protein alone, while twelve more received a sham vaccine.

These 40 monkeys also received six viral challenges, starting at three years nine months after their initial prime vaccine dose. But this challenge was of a lab-created combined monkey/human virus called SHIV-SF162P3.

Efficacy

In the first SIV experiment, five of the eight unprotected monkeys given the sham vaccine (60%) became SIV-positive after their first challenge dose and all by their fifth dose. The SHIV virus resulted in a similar infection rate, with all infected by five doses.

One of the monkeys who received the ad/ad SIV vaccine was infected at the first challenge, four by the second challenge and ten out of twelve by the sixth challenge. This translates into 75% protection from one single dose of SIV and 17% protection from the six doses. In the HIV env vaccine experiment, 49% protection from a single viral challenge was observed and 12% protection from all six challenges.

None of the monkeys receiving the ad/env vaccine was infected by the first challenge, two by the second, and by the sixth challenge, six were infected. This translates into 90% protection from one single dose of SIV and 50% protection from the six doses. In the case of the HIV-based vaccine and SHIV challenge, 79% protection was seen from one viral challenge and 40% protection from all six.

In the monkeys given the SIV ad/env vaccine that were infected, two became elite controllers, becoming virally undetectable in blood about two months and six months respectively after the last challenge. One that was biopsied did harbour detectable HIV DNA in multiple immune-system tissues but at roughly one-thirtieth the level of the non-controllers. However when cells from both elite controllers were injected into another group of SIV-negative monkeys, they developed SIV infection with normal viral loads.

In contrast, when cells from all eight uninfected animals in the SIV experiment were injected into uninfected monkeys, there was not the slightest sign of SIV infection. This last finding is very important. Many vaccines appear to work by allowing initial SIV infection but then containing it. In contrast, in 50% of cases in the case of the ad/env vaccine, this vaccine appears to offer full sterilising immunity: it completely prevents SIV from getting inside cells. This was not thought possible by some vaccine researchers, who have suggested that a vaccine offering functional immunity was the best that could be expected. If this is true sterilising immunity, it is a very promising development.

Immune responses

Analyses of the immune responses generated by the SIV vaccines showed that the ad/ad vaccine induced high levels of a couple of familiar inter-cell signalling chemicals, interferon-gamma and CCL4 (also called MIP-1 beta). Most monkeys generated either or both of these two types of immune response, but only two individuals developed any additional responses out of a list of six types of immune response instanced by the researchers.

As well as these humoral (antibody-driven) responses, they also developed CD8 (T-suppressor) cells specific to SIV but, as other vaccine trials have demonstrated, these do not necessarily produce protection and may in certain cases even increase vulnerability.

In contrast monkeys receiving the ad/env SIV vaccine developed a minimum of two immune responses and most developed four to six types of response.

The other types of response included antibody-dependent generation of CD107a or LAMP-1, a protein that mediates cell-to-cell communication. In addition, the researchers also saw high levels of antibody-driven cellular cytotoxicity (ADCC), phagocytosis (ADCP) and complement deposition (ADCD). These are immune processes set in motion by antibodies that strengthen the operation of the innate immune system – the third, most evolutionarily primitive, and most swift-acting branch of the immune system and one now thought to be crucial to the success of an effective HIV vaccine, especially one offering sterilising immunity.In addition, the ad/env SIV vaccine also generated CD4 cells immune to HIV – a much more useful cellular response than a CD8 response.

This study’s significance

In the last couple of years, it is ‘wild card’ vaccines that have made the news: a vaccine based on a CMV herpesvirus vector that allowed over 50% of a group of monkeys to completely control their existing HIV infection; a vaccine based on a probiotic drink that apparently also controlled early infection. These both appeared to offer a very profound type of functional immunity: in the case of the CMV vaccine by mounting a prolonged and multi-component immune response, in the latter by – if the hypothesis is right – damping down the body’s response to SIV so that the virus was starved of cells to infect. 

While vaccine research often does rely on serendipity, however, this implies that planned research pathways and careful improvement of existing candidates cannot succeed. In a way, one of the most refreshing aspects of this study is that a vaccine designed to be an improvement on ones previously tried, based on study results, duly proved to be about 50% more potent. This shows that vaccines can be improved on and the immune responses they generate can be fine-tuned.  HIV vaccine development, or at least a large part of it, is starting to agree on a consensus research direction in the journey towards the ultimate goal of a vaccine that reliably protects humans. It is a mark of faith in this particular research programme that, although run by scientists from Harvard Medical School and the Ragon Institute among others, it is supported by Janssen Infectious Diseases, a branch of the pharmaceutical giant Johnson and Johnson.

The researchers themselves say that “clinical efficacy studies are required to determine the protective efficacy of these HIV-1 vaccine candidates in humans.”

This study is not the breakthrough moment when science discovers a vaccine that will stop the HIV epidemic. But it is representative of the kind of solid progress researchers have been making towards an effective vaccine in the last five years, ever since the RV144 vaccine trial demonstrated that generating a protective response to HIV was possible, and that it had certain specific characteristics that could be improved on.