Investigators at the Stanford University School of Medicine and several other institutions have shown that a new type of vaccination can substantially enhance and sustain protection from HIV.
A paper describing the vaccine, which was given to monkeys, will be published online May 11 in Nature Medicine. The findings carry broad implications for immunologists pursuing vaccines for the coronavirus and better vaccines for other diseases, said Bali Pulendran, Ph.D., professor of pathology and of microbiology and immunology at Stanford.
The key to the new vaccine’s markedly improved protection from viral infection is its ability – unlike almost all vaccines now in use – to awaken a part of the immune system that most current vaccines leave sleeping.
“Most vaccines aim at stimulating serum immunity by raising antibodies to the invading pathogen,” said Pulendran, referring to antibodies circulating in blood.
“This vaccine also boosted cellular immunity, the mustering of an army of immune cells that chase down cells infected by the pathogen. We created a synergy between these two kinds of immune activity.”
Pulendran, the Violetta L. Horton Professor II, shares senior authorship of the study with Rama Amara, Ph.D., professor of microbiology and immunology at Yerkes Primate Research Center at Emory University; Eric Hunter, Ph.D., and Cynthia Derdeyn, Ph.D., professors of pathology and lab medicine at Emory; and David Masopust, Ph.D., professor of microbiology and immunology at the University of Minnesota. The lead authors are Prabhu Arunachalam, Ph.D., a postdoctoral scholar at Stanford; postdoctoral scholars Tysheena Charles, Ph.D., and Satish Bollimpelli, Ph.D., of Emory; and postdoctoral scholar Vineet Joag, Ph.D., of the University of Minnesota.
Some 38 million people worldwide are living with AIDS, the once inevitably fatal disease caused by HIV.
While HIV can be held in check by a mix of antiviral agents, it continues to infect 1.7 million people annually and is the cause of some 770,000 deaths each year.
“Despite over three decades of intense research, no preventive HIV vaccine is yet in sight,” Pulendran said. Early hopes for such a vaccine, based on a trial in Thailand whose results were published in 2012, were dashed just months ago when a larger trial of the same vaccine in South Africa was stopped after a preliminary assessment indicated that it barely worked.
Vaccines are designed to arouse the adaptive immune system, which responds by generating cells and molecular weaponry that target a particular pathogen, as opposed to firing willy-nilly at anything that moves.
The adaptive immune response consists of two arms: serum immunity, in which B cells secrete antibodies that can glom onto and neutralize a microbial pathogen; and cellular immunity, in which killer T cells roam through the body inspecting tissues for signs of viruses and, upon finding them, destroying the cells that harbor them.
But most vaccines push the adaptive immune system to fight off infections with one of those arms tied behind its back.
“All licensed vaccines to date work by inducing antibodies that neutralize a virus. But inducing and maintaining a high enough level of neutralizing antibodies against HIV is a demanding task,” Pulendran said.
“We’ve shown that by stimulating the cellular arm of the immune system, you can get stronger protection against HIV even with much lower levels of neutralizing antibodies.”
In the new study, he and his colleagues employed a two-armed approach geared toward stimulating both serum and cellular immunity. They inoculated three groups of 15 rhesus macaques over a 40-week period.
The first group received several sequential inoculations of Env, a protein on the virus’s outer surface that’s known to stimulate antibody production, plus an adjuvant, a chemical combination often used in vaccines to beef up overall immune response.
The second group was similarly inoculated but received additional injections of three different kinds of viruses, each modified to be infectious but not dangerous. Each modified virus contained an added gene for a viral protein, Gag, that’s known to stimulate cellular immunity.
A third group, the control group, received injections containing only the adjuvant.
At the end of the 40-week regimen, all animals were allowed to rest for an additional 40 weeks, then given booster shots of just the Env inoculation.
After another rest of four weeks, they were subjected to 10 weekly exposures to SHIV, the simian version of HIV.
Monkeys who received only the adjuvant became infected. Animals in both the Env and Env-plus-Gag groups experienced significant initial protection from viral infection. Notably, though, several Env-plus-Gag animals – but none of the Env animals – remained uninfected even though they lacked robust levels of neutralizing antibodies.
Vaccinologists generally have considered the serum immune response – the raising of neutralizing antibodies – to be the defining source of a vaccine’s effectiveness.
Even more noteworthy was a pronounced increase in the duration of protection among animals getting the Env-plus-Gag combination. Following a 20-week break, six monkeys from the Env group and six from the Env-plus-Gag group received additional exposures to SHIV.
This time, four of the Env-plus-Gag animals, but only one of the Env-only animals, remained uninfected.
Pulendran said he suspects this improvement resulted from the vaccine-stimulated production of immune cells called tissue-resident memory T cells. These cells migrate to the site where the virus enters the body, he said, and park themselves there for a sustained period, serving as sentinels. If they see the virus again, these cells jump into action, secreting factors that signal other immune-cell types in the vicinity to turn the tissue into hostile territory for the virus.
“These results suggest that future vaccination efforts should focus on strategies that elicit both cellular and neutralizing-antibody response, which might provide superior protection against not only HIV but other pathogens such as tuberculosis, malaria, the hepatitis C virus, influenza and the pandemic coronavirus strain as well,” Pulendran said.
The World Health Organization (WHO) identifies uniformed armed personnel among some of the key populations to be focused upon in the national HIV strategic plans for several countries in sub-Saharan Africa, due to their higher risk for HIV infection compared to the general population [1].
For example, members of the uniformed armed forces in Congo were found to have higher HIV prevalence compared to the general population (3.8% versus 1.3%) [2].
Similarly, the Uganda Peoples Defence Forces (UPDF) has been listed among the most at-risk population due to high HIV incidence rates compared to the general population (3.56 per 100 person-years, 95% confidence interval [CI]: 1.49–5.52, versus 2.1 per 100 person-years, 95%CI: 1.1–3.1) [3, 4].
This is attributed to the nature of their occupation characterised by mobility and long periods of separation from their families, which predisposes them to risky sexual behaviours [5].
Members of the Uganda Police Force (UPF) are potentially likely to follow the same trends in HIV risk since they share similar operational structures as those of the army. A study conducted in Tanzania among members of the urban police force demonstrated high-risk sexual practices including low condom use, resulting in high HIV prevalence and incidence [6].
Although most of the countries in sub-Saharan Africa have implemented efforts to address HIV in the armed forces, there have been gaps noted in the amount of research in this area [7].
Evaluation of novel HIV prevention strategies (including HIV vaccine research) necessitates the recruitment of populations with presumed high exposure to HIV and high motivation to remain under study [8].
A study conducted in a population of police officers in Dar-es-Salaam, Tanzania, demonstrated they were a suitable population for HIV vaccine research due to their high HIV prevalence and high rate of willingness to participate in future vaccine trials [9].
Thus, the first HIV vaccine trial in Tanzania was conducted in a population of police officers [10]. There is surprisingly little reliable data on the prevalence and incidence of HIV among other uniformed personnel in East Africa, including the UPF, and their suitability as potential participants of HIV vaccine trials.
In this paper, we describe the findings of a study to determine the acceptability and suitability of UPF personnel for future HIV vaccine trials by setting up a cohort study to estimate the recruitment and retention rates as well as HIV incidence rate and associated factors over a one-year period.
Discussion
Our study shows that it is feasible to recruit and adequately follow up volunteers from a population composed of police force and their relatives for research. We established incidence rates of HIV and syphilis in this population.
However, the data show an unexpectedly low HIV incidence and low syphilis prevalence which might be as a result of our recruitment methods. During recruitment some individuals at high risk of infection were selected out at screening and lost to follow up.
The heterogeneous composition of our cohort, including non-police officers could have caused some form of risk dilution by including low risk individuals explaining the low incidence if HIV despite high rates of condomless sex as evidenced, for women, by the high pregnancy rates.
Of the 2059 individuals who attended the community voluntary HIV testing, only 560 (27.2%) made it to the clinic for further study eligibility assessment. This was because majority of those approached only required HIV testing services and although the study sample size of 500 was attained, the testing service continued.
The observed low incidence of HIV and syphilis is encouraging and may be partly due to the education level and prior HIV/STI -prevention knowledge of those recruited into the cohort. In addition, HIV testing is mandatory for recruitment into the police force in Uganda, and only HIV negative individuals are eligible to stay, this is likely to have contributed to the low prevalence and incidence because we had a number of newly recruited members of the force in the cohort. Of note, the low HIV incidence would make this population suitable for phase I and II trials which require low risk individuals for safety and immunogenicity studies [11].
The observed decline in the reported risk behaviours over one year could be attributed to the risk reduction counselling that was offered at each quarterly visit. A similar finding was observed in a female sex worker cohort study, by Traore et al. [12] in Burkina Faso, where zero HIV infections were observed following a combination intervention over a two year period.
In another study conducted by Kaul et al. [13] among female sex workers in Nairobi, a reduction in risk taking was observed after an intensive period of risk reduction counselling and regular STI treatment.
In another study, Ghys et al. [14] found that HIV prevention intervention contributed to significant lowering of the HIV-1 seroincidence rate during the intervention study than before the study (6.5 versus 16.3 per 100 person-years; P = 0.02).
However, such a reduction as observed in our study should be interpreted with caution, since it could also be a result of social desirability bias [15, 16].
Our study demonstrated a good overall retention rate in this population. In common with similar studies [17], we observed that retention was better among volunteers who had lived in the facility longer, a possible reflection of their relative stability, which may also have affected their HIV-infection risk.
Volunteers who reported no knowledge of HIV risk were more likely to be retained compared to those reporting to be knowledgeable, possibly because the latter sought to attend in order to acquire more knowledge.
We observed that loss to follow up was associated with volunteers who reported the most high-risk behaviours as well as those who reported having travelled away from home in the last month. This association may also explain the low incidence observed in the study.
Our study had limitations. Firstly, during screening and recruitment of our study population, we did not systematically recruit to ensure a weighted representation from the different police departments and ranks, giving rise to possible selection bias.
From our anecdotal observations, we noted that the majority of enrolled police officers were from lower ranks, and we had no representation from some of the departments such as the traffic and mobile patrol units, who might differ in terms of the variables and outcomes we were investigating. Secondly, our study was not designed to collect specific reasons why volunteers were lost to follow up, which would be useful in explaining the reasons and so inform possible interventions. Thirdly, the study findings are based mostly on self-report which might potentially introduce social desirability bias if participants choose to modify their responses to mask risk behaviour. However, inclusion of biological information such as HIV and syphilis incidence add credence to our findings.
Conclusions
The study showed it is possible to recruit and adequately follow up volunteers from the community of the Uganda Police Force for participation in future HIV vaccine trials. The low HIV incidence and decline in HIV risk behaviour during follow-up, combined with the favourable retention rate could make this population potentially suitable for Phase I & II HIV vaccine trials, where low risk individuals are required.
However, the surprisingly low HIV incidence in our cohort suggests that those at higher risk of infection (i.e., those in mobile divisions in the force) may have been omitted from our cohort, and such population would not be adequate for Phase III HIV vaccine trials. We recommend more stringent sampling to ensure greater representation of different ranks and divisions (i.e. traffic police) in future epidemiological studies in such similar populations.
More information: T cell-inducing vaccine durably prevents mucosal SHIV infection even with lower neutralizing antibody titers, Nature Medicine (2020). DOI: 10.1038/s41591-020-0858-8 , www.nature.com/articles/s41591-020-0858-8
