The novel coronavirus, SARS-CoV-2, has led to an unprecedented international health crisis. The implementation of a vaccine is essential to accelerate herd immunity, enabling lockdown measures to be relaxed and socioeconomic activity to safely resume whilst limiting the case fatality rate. A concerted global effort has led to over 150 vaccines currently under development. However, it is apparent that oral administration has been markedly under addressed as a potentially effective immunological strategy.
Research has now revealed a high expression of the SARS-CoV-2 receptor, ACE2, and the serine protease for virus spike protein priming, TMPRSS2, in absorptive enterocytes of the ileum and colon. 1 This highlights a non-canonical route of host invasion for SARS-CoV-2, and a potential site at which artificial immune induction through an oral vaccine could be protective.
Oral immunisation is a viable strategy that has been implemented successfully in preventing respiratory illness. 2 For example, the live oral enteric-coated adenovirus type 4 and type 7 vaccines, approved for use in US military personnel 17-50 years of age, have been shown to be safe and highly effective in reducing disease burden in numerous clinical trials. 3 These vaccines cause an asymptomatic infection of the gut and subsequently generate mucosal immunity to protect against future respiratory illness. 4 More recently, an orally administered influenza vaccine has progressed successfully through phase II clinical trials, highlighting the promising potential and ongoing active development of oral vaccines for respiratory disease. 5 Several benefits may be attained through employing an oral approach. Evidence suggests that the mucosal route may allow more potent induction of humoral (antibody-mediated) and cellular immune responses, priming the body to respond effectively to respiratory challenges. 6 In addition, as documented with the oral polio and rotavirus vaccines, the possibility of faecal shedding of oral vaccines may accelerate herd immunity through oro-faecal transmission in close contacts, particularly in the developing world. 7, 8 Oral vaccines may also be manufactured more simply, highlighting the scalability of this approach. 2 The ease of oral inoculation also removes the requirement for trained healthcare professionals to be present to administer the vaccine, minimising cross-infection risk at healthcare centres, whilst potentially maximising uptake and compliance. This may significantly expand practical options for vaccine distribution, particularly in resource-limited settings that are worst affected, given that other preventive measures, such as social distancing, may be harder to implement. 9 In addition, thermally stable oral formulations in the past have been independent of a temperature-controlled supply chain, potentially further simplifying distribution logistics by eliminating a significant contributor of cost in vaccine distribution programmes. 10 It is possible that oral vaccines may be effective as a complementary approach, preferentially employed in resource-limited, population-dense settings.
Taken together, the development of a successful oral formulation may offer relative advantages concerning safety, efficacy, compliance, ease of manufacturing and administration. These factors are essential to consider when developing globally scalable immunisation strategies against SARS-CoV-2.