Study title: A dose finding human experimental infection study with SARS-CoV-2 in healthy volunteers with previous, microbiologically confirmed, SARS-CoV-2 infection.
Chief Investigator: Professor Helen McShane
Sponsor: University of Oxford
Funder: Wellcome Trust
In December, 2019, a local outbreak of pneumonia of initially unknown cause was detected in Wuhan (Hubei, China), and was quickly determined to be caused by a novel coronavirus, namely severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since then, the virus has made its way across the globe to affect over 180 countries and was declared a pandemic by the World Health Organisation on 11 March 2020. As of 3rd March 2021, there have been over 4 million confirmed COVID-19 cases and over 120,000 deaths in the United Kingdom.
Understanding the nature, effectiveness and durability of the human immune response to SARS-CoV-2 is crucial for the long-term management of the disease. At present, we have some knowledge of the pattern and kinetics of the humoral response to natural infection from epidemiological studies but are less certain about all other aspects of the response including the nature of the T cell response, the extent of existing immunity in the population to SARS-CoV-2, the role of innate immunity, the extent of memory B cell creation, the durability of all these elements of protection and how these correlates of immunity change after vaccination.
The primary purpose of this study is to evaluate the safety and human clinical response to SARS-CoV-2 challenge in previously SARS-CoV-2 infected people. We start by establishing the optimal challenge dose that causes re-infection. The study hopes to identify the lowest level of infectious dose necessary to produce viral replication in the upper respiratory tract of research volunteers while minimising risk of disease progression. Investigators aim to achieve an infection model which results in no symptoms, or symptoms no more severe than the common mild response of healthy people of the same age within the general population.
Demonstration of a safe SARS CoV-2 human challenge model in seropositive individuals will then allow its use, to study in detail how baseline immunity, prior to infectious challenge, confers protection from re-infection. By comprehensively characterising the baseline immune response in healthy subjects who have previously been infected with SARS CoV2, and then determining re-infection rates after infectious challenge, we can establish which baseline immune responses, induced by prior infection, protect against subsequent re-infection. We can also use quantitative viral load data post-infectious challenge to further define immune correlates of protection. We expect the use of young, healthy and previously infected individuals to demonstrate the most robust immune responses providing the best opportunity to identify potential correlates of protection. Identification of such correlates has for other pathogens allowed targeted vaccine and therapeutic development as well as providing immunological efficacy end points allowing prioritisation of new therapeutic candidates.
We can also use this controlled human infection model to define precisely the innate and adaptive immune response after infection in a way that is not feasible in natural infection, where timing infection precisely is not possible. Challenge models have the added benefit over epidemiological studies of allowing detailed investigation of the immune response after a defined time-point infection allowing a greater narrative on both viral kinetics and the nature of protective and non-protective immune responses. The early innate immune response is thought to play a vital role in determining disease phenotype and can be difficult to characterise with both asymptomatic and pre-symptomatic infection often missed in epidemiological studies.
The information gained from these studies can also inform policy makers on issues, such as determining whether to allow return to unfettered travel and normal daily activities, as well as information to determine the need and timing of vaccination and re-vaccination in the context of previous infection. We will define viral shedding in the breath in both asymptomatic and mildly symptomatic patients, better informing Public Health infection control policy. Furthermore, with the recent identification of new variants that escape targeted treatments such as monoclonal antibody therapy and convalescent plasma, establishing a safe SARS-CoV-2 CHIM using wildtype virus is a necessary first step prior to future studies using new variants in individuals who are seropositive either from natural infection with different lineages of the virus or vaccination . This could be an essential step in speeding the development pipeline of novel vaccines and therapeutics against new variants.