Correlates of protection against SARS-CoV-2 infection and disease in recently exposed household contacts (COPASID)

The emergence of successive SARS-CoV-2 vaccine escape variants highlights the need for more broadly protective, 'variant-proof' vaccines that protect against current and future, potentially more harmful, variants. We aim to identify and harness the body's own natural broadly protective immune responses to inform development of such 2nd generation universal vaccines.

While SARS-CoV-2 causes severe disease in many people, most have mild illness, indicating that natural immune responses can successfully contain the virus and limit symptoms, like a protective brake. Additionally, over 50% of household contacts (HHCs) remain uninfected despite heavy exposure to SARS-CoV-2. This implies the body's defences can prevent infection, even without vaccination, like a protective shield. However, little is known about these natural protective mechanisms because research to date has focused on severe, hospitalised COVID-19 patients. Hence, the following important questions are yet to be answered:

(a) What mechanisms protect the body from infection despite exposure?
(b) If infection occurs, what are the early mechanisms that enable the body to successfully contain the virus and limit symptoms?

To address these, we need to measure the body's immune profile at the time of exposure to SARS-CoV-2 and study the subsequent 'outcomes' of infection. This allows us to tease out which profiles:

(a) predict protection from infection
(b) contain the virus and limit symptoms in those who get infected

We can then bring benefits of these natural protective mechanisms to people who do not naturally have them, preventing transmission and severe disease. For example, this new knowledge will inform development of 2nd generation vaccines to provide broad protection against current and future 'escape' variants which evade the narrow protection provided by current vaccines. Another application could be a nasal spray that enhances natural immune mechanisms in the lining of the nose and throat, preventing or treating infection before it progresses.

This proposal leverages the comprehensive repository of clinical samples (biobank) of a unique population of 180 HHCs exposed to COVID-19 cases. From the time of SARS-CoV-2 exposure onwards, each contact completed daily symptom questionnaires and provided frequent samples of blood, throat swabs and nasal lining fluid (NLF). NLF reflects the status of the 'upper respiratory tract,' where SARS-CoV-2 alights in the body to establish infection. This is the pivotal battlefield between the virus and the body that largely decides outcome of exposure - but it has not previously been researched in people exposed to SARS-CoV-2.

The blood and NLF samples were frozen in a secure, indexed biobank. In both NLF and blood we will measure a wide range of immune mechanisms that we suspect may mediate protection. These include chemical messengers, antibodies and different types of immune cells. To ensure we do not miss responses that we have not considered, we will cast our net wide by measuring many different proteins and the expression of many genes in the valuable NLF samples. The clinical symptom data and throat swab virus load results were stored anonymously in a secure, linked database. Together they comprise the 'outcomes' of infection, e.g., resisting infection or getting infected but with low viral load and minimal or no symptoms.

Although our project is highly original and addresses questions of far-reaching medical and scientific importance, the risk to successful execution is very low because:
1. The biobank and linked participant data are established
2. All the necessary methods for measuring immune mechanisms are up-and-running in our lab
3. Our world-leading expert project team has a diverse range of experience providing all the requisite skills to deliver

Lastly, the cost to establish the biobank (£1.5 million) has already been met, making this proposal excellent value for money.

Successive SARS-CoV-2 immune-escape variants make understanding the components of protective immunity to coronaviruses a public health priority. The spectrum of outcomes of SARS-CoV-2 exposure is largely determined by the host response. Most infections are asymptomatic or mild, indicating that effective host responses can successfully contain infection. Additionally, the fact that most SARS-CoV-2-exposed household contacts remain uninfected implies that effective innate immunity, or pre-existing cross-reactive adaptive immunity, can prevent infection. Our goal is to identify the correlates of natural protective immunity that predict these optimal outcomes.

Identifying correlates of protection requires longitudinal study, from the earliest time points after defined exposure, of SARS-CoV-2-naïve unvaccinated individuals who have optimal outcomes. The biobank we created from our globally unique longitudinal cohort of COVID-19 household contacts in the 2nd pandemic wave enables us to pursue this powerful strategy.

Since the biobank includes airway mucosal samples from the time of SARS-CoV-2 exposure (the initial host-pathogen interface), we will measure a range of mucosal as well as systemic, innate and adaptive immune responses. We will delineate which immune profiles predict the optimal outcomes observed in our cohort, ie remaining uninfected despite exposure and, in contacts who become infected, having low viral load and mild symptoms. Our preliminary data have stimulated compelling hypotheses that we will now test, while also assessing other potentially protective host responses. With our co-applicants who recently completed the world's first SARS-CoV-2 controlled human challenge model, we will corroborate the mechanistic relevance of our findings.

Our findings will have strong translational potential to inform development of more broadly protective 2nd generation vaccines and other host-directed interventions to prevent or treat SARS-CoV-2 infection.