Achieving diversity in vaccine clinical trials

Written by:

Tonya Villafana

Global Franchise Head Infection

Testing a potential new vaccine on human volunteers is a key step in the journey from laboratory to clinic, and ensuring that volunteers represent those who will need to be vaccinated is a major priority. We need to demonstrate a vaccine’s safety and efficacy for all those who need it, whatever their age, sex, ethnicity and overall health, and wherever they live.

Historically, clinical trials for vaccines were mainly carried out in North America and Europe. However, 20 years ago, when I moved to Botswana to set up HIV vaccine trials in collaboration with the US National Institutes of Health HIV Vaccine Trials Network, the importance of involving local communities in vaccine studies was immediately clear.

Establishing trials in the communities where vaccines are needed helps to ensure that safety and efficacy data are relevant to those vaccinated. It also helps to build understanding of the importance of vaccines and confidence in their use. In a pandemic, this may be even more important as people across all continents are affected. The COVID-19 vaccine trial programmes have been like nothing we have seen before, or possibly will again. There was certainly no shortage of countries wanting to participate, and we included countries to ensure diverse global representation.

Testing for safety and efficacy

Like new medicines, vaccines progress from smaller trials to larger studies where efficacy is determined. Specifically vaccines progress from Phase 1 safety studies in a small number of healthy volunteers, usually  through Phase 2 safety and immunogenicity studies in a few hundred and finally to large Phase 3 trials to compare vaccine safety and efficacy against placebo or control vaccine in thousands of volunteers. Vaccine studies also test each volunteer’s immune response to the target virus or bacterium. This may mean measuring both humoral and cellular components of the immune system including neutralising antibodies and, in some cases, T cells. For SARS CoV2 we do not know what level of immune response corresponds to protection against COVID-19. This is currently being investigated in the context of vaccine efficacy for multiple vaccine candidates and very exciting for scientists as we seek to determine “correlates of protection” against disease. Many questions still remain including how often doses are needed, what interval between doses is optimal, how long vaccination provides protection and can different vaccines be given together to optimise immune responses and protection.

Phase 3 trials of vaccines tend to be larger than those for new medicines. Vaccines are tested in healthy populations, so great attention and scrutiny is paid to monitoring adverse effects and ensuring the benefit/risk for healthy populations is appropriate. Typically, as diverse a range of people as possible are enrolled.

For vaccines against respiratory viruses that cause severe disease, such as COVID-19, it is important to determine if vaccines reduce serious consequences of disease, such as severe breathing problems requiring hospitalisation, artificial ventilation in an intensive care unit, or death. We also investigate whether the vaccine reduces less severe respiratory disease and the risk of the virus spreading from person to person.

Inspiring response from trial volunteers

For rapid results in large Phase 3 trials, recruitment is initially carried out in countries or regions with the highest levels of the infection that a vaccine is designed to prevent, so its efficacy can be tested in those at greatest risk.

Infrastructure previously developed for large scale vaccine trials of HIV, malaria and other diseases in Latin America, Asia and Africa have been instrumental for recruiting volunteers at highest risk of COVID-19, such as people of colour, in vaccine trials over the last 12 months. To aid trial recruitment, collaborations between industry and organisations such as the COVID-19 Prevention Network (CoVPN), formed by the US National Institute of Allergy and Infectious Diseases (NIAID), have been incredibly important. They have been able to leverage approaches based on the volunteering networks for HIV vaccine and prevention studies, which have proved successful around the world.

It is truly inspiring to see the commitment of community networks in spreading the word about the importance of COVID-19 vaccine trials and the value of volunteering, and to witness the generosity of those who stepped forward to take part.

As with most vaccine development, COVID-19 vaccine trials started in healthy volunteers aged 18-55 and, after initial safety and immunogenicity information was collected trials were extended to older adults who are more susceptible to disease. For AZD1222 studies, enrolment extended to those aged 55-69, followed by older adults over70.

We do not expect significant differences in clinical data from vaccine trials of people of different ages, sex or ethnicity but it is important for all those at risk of infection to be included and for this to be investigated. Regulatory agencies and institutional review boards/ethics committees also expect trials to reflect the burden of disease in different groups of people.

Extending diversity into real world studies

During the pandemic, we have worked closely with regulators to ensure that each stage of data review is carried out as rapidly and efficiently as safely possible. As a result, the first approval of a COVID-19 vaccine for emergency use occurred only nine months after research began – an incredible achievement. Full approval of all COVID-19 vaccines will require longer term data showing durable immune responses and reduced disease, hospitalisation and mortality rates.

We are also collecting real world safety and efficacy data from hundreds of thousands of vaccinated individuals to confirm clinical trial findings and extend our knowledge across ever more diverse populations including those in poor health due to other diseases or old age. Novel dosing frequencies of vaccines as well as combinations of different vaccines are also being investigated.

More than two decades after I became involved in vaccine research and development, I couldn’t be prouder of what has been achieved by my fellow scientists, clinicians, community groups and, of course, the volunteers themselves, in bringing COVID-19 vaccines to fruition for populations around the world. We made the impossible, possible!