Background

As the number of persons vaccinated against COVID-19 around the world increases and the number of approved vaccines for use among adults rises, there is growing recognition of the need to extend vaccination campaigns to children. Emergency use authorisation has already been provided by various national regulators to allow for the use of the Pfizer-BioNTech and Moderna vaccines in children 12 years of age and older. Furthermore, vaccine trials involving younger children and testing different vaccines are underway in various countries.1 While most of these trials are currently conducted in high-income countries, it is likely—and necessary—that COVID-19 vaccine trials involving children will increasingly be extended to lower/middle-income countries (LMICs) in order to ensure that vaccines are effective in these different populations and contexts. In that case, ethics committees and policy makers will be faced with the review of trial proposals that not only raise potentially challenging ethical questions (as in all interventional studies with children),2 but where those questions are further complicated by a number of factors associated with the pandemic context in a low-resource setting. These include the urgency to act (which may add to the pressure experienced by those tasked with reviewing studies); a lack of clarity as to where future benefit from the studies may accrue (given current concerns about inequality of vaccine access); and, more broadly, the impact of inequalities in terms of scientific capacity and economic power which may skew the ability of some committees to provide independent reviews.

As members of the ethics working group of the COVID-19 Clinical Research Coalition (which brings together expertise in research ethics from across a wide range of LMICs), we are aware that ethics committees in LMICs do not all feel well-placed to review such trial proposals. Our goal in this paper is to share our insights and key recommendations for the elements of vaccine trial proposals that ethics committees should particularly scrutinise when reviewing such proposals. Below we set out some ethical questions and possible replies that researchers and ethics review committees might need to keep in mind before, during and after the implementation of phase III vaccine clinical trials with children. We use the term ‘children’ in this article to refer to persons who cannot legally give consent because of their age: this will commonly be those under the age of 18, although depending on jurisdiction this may vary from 16 to 21. Our concern is especially with children living in lower-income and middle-income settings.

It is not our goal to discuss the wider ethical debate about when, amidst global scarcity of vaccines, countries should start vaccinating persons under 16 or 18 years.3 The question we address is a different one. Vaccination campaigns among children require the availability of vaccines that have been tested and approved as safe and effective for use among children. It is well recognised that children’s immune systems are not just smaller versions of adult ones.4 Younger children are developmentally, physiologically, and psychologically different from adults, and their immune system and physiology changes during different developmental stages, as they approach adulthood. Clinical trials generate knowledge about which health interventions are safe and effective for children at different developmental stages, thus protecting their health and well-being. Nevertheless, these trials raise ethical questions that are different to trials among adults.

Historically, people have been cautious about including children in clinical trials. Children have long been regarded as inherently vulnerable in research, both because of their reliance on others to meet their basic needs, and because their ability to make their own decisions is still developing.5 These concerns about the risks of involving children in research have resulted in restrictive approaches designed to protect children that, in practice, may lead to the conclusion that it is ‘safer’ not to undertake research with children at all. However, the result of not including children in properly designed research is that they end up being treated without an adequate evidence base as to the safety, efficacy and dosage of therapies in (developing) children—thus potentially making children more vulnerable through exposure to unsafe care. In recognition of this dilemma, there has been considerable debate in recent years over how to ensure that such research can be conducted ethically. Key developments include an emphasis on working with children and families to design studies in ways that are appropriately child-friendly, and to ensure that children are involved, in ways suitable for their age and state of emotional and psychological development, in decisions about their own participation.6

The CIOMS Ethical Guidelines (2016, Guideline 17) recommend that ‘children and adolescents must be included in health-related research unless a good scientific reason justifies their exclusion’,7 while emphasising the importance of minimising risks and, where relevant, waiting first for data from adult trials. A more restrictive position is presented, for instance, by the national South African Health Research Ethics guidelines, which propose that research should involve children only if the research cannot equally be conducted with adults, if the outcome of the research is directly relevant for children, and if the risk is reasonable—and preferably, minimal.8 Importantly, these and other guidelines suggest that since children in general are less able than adults to protect their own interests, additional safeguards are needed to ensure they are not exploited.

Reasons for carrying out COVID-19 vaccine trials with children

There are several reasons why COVID-19 vaccine trials should involve children. These all relate to a consideration of whether and how being vaccinated could directly or indirectly be of benefit to children’s health. If proven effective, vaccines would clearly offer direct benefits to children who for various reasons have an increased risk of severe illness or death from COVID-19. There is currently limited information on children since fewer children have been affected with severe illness; however, there is increasingly clear evidence that children living with pre-existing health conditions, including complex disability with high healthcare needs,9 are at higher risk from developing COVID-19 complications. The evidence regarding the risks of ‘long-COVID’ on children is still developing but highlights a further non-negligible source of concern.10 Furthermore, with the emergence of new variants, and with increasing concerns about the effect of long-COVID on children, it is possible that effective vaccines would confer direct physical health benefits to all children and not just those at increased risk of severe disease. Vaccines can also reduce the impact of COVID-19 infection in children, by putting them in a safer condition to socialise normally both with their peers and older persons, and in particular by reducing the risk of extended absences from school. The ability to socialise is important for the mental health, growth, development, and overall well-being of children. Thus, a safe and effective vaccine for children is of direct benefit to them.

Additionally, vaccinated children can also protect those that cannot be vaccinated due to medical conditions, thus also protecting others who live with them or attend school with them. Furthermore, beyond direct potential benefit to children, there is also a strong public health reason to ensure that safe and effective vaccines are available for children. Namely, even though the earlier goal of herd immunity now seems like a mirage and the SARS-CoV-2 virus and its variants are more likely to become endemic,11 a failure to vaccinate children—which would allow the virus to spread freely in a large part of the population—could increase the possibility that new variants emerge that could either be more contagious or resistant to existing vaccines and therapeutics. This point is particularly relevant in many African countries where up to 40% of the population is younger than 16 years of age. Thus, there are also important public benefits to ensuring that vaccines are developed that are safe and effective for use in children.

In the remainder of this paper, we discuss the most important considerations for ethics committees reviewing proposals that involve children in COVID-19 vaccine clinical trials.

Some ethics Q&A when implementing COVID-19 vaccine trials with children

Guidelines and normative documents on vaccine clinical trials with children in many countries and regions were written before the COVID-19 outbreak.12–14 The scale of the threat posed by the SARS-CoV-2 virus, however, cutting across borders, age groups, race, socioeconomic situation, gender and sexual orientation, is unprecedented. There is an urgent need to immunise as many people as possible and as quickly as possible. Yet, there is an equally important need to avoid exposing people to excessive risks, especially children.15 Moreover in some countries, as some vaccines are undergoing clinical trials involving children, other vaccines have already been approved for use among adults and some minors. In other countries, mostly LMICs, vaccines are yet to be made available even for vulnerable and adult populations.16 These differences and the impellent need to vaccinate populations generate novel ethical questions that were not at the fore prior to the emergence of the COVID-19 pandemic. Some jurisdictions, for example, the US Food and Drug Administration, offer updated guidelines on COVID-19 clinical trials involving children.17 Many are yet to do so; thus, it is in this vein that as members of the Ethics Working Group of the COVID-19 Research Coalition we offer some ethical ‘things to think about’ as researchers and IRBs embark on or follow through with COVID-19 clinical trials involving children.

Final remarks

The COVID-19 pandemic is daily pushing science and ethics into unexplored terrain. In the case of ethics committees, there is the need to draw on existing normative guidelines and to adapt them to the rapid evolution of the pandemic and response measures. As vaccines appear to be successful in reducing deaths and severe illness among adults, a major concern now is how to protect children from getting infected and transmitting the virus, and from falling ill themselves. An important tool is the vaccination of children. Yet, this choice needs to be backed by science and ethics. This brief paper is an effort by a group of ethicists working within the COVID-19 Research Coalition to share concerns and ideas with ethicists who are currently or will soon be reviewing protocols for vaccine trials among children.