SARS-CoV-2 transmission was expected to have a devastating impact in sub-Saharan African countries. Instead, morbidity and mortality rates in nearly the whole region are an order of magnitude lower than in Europe and the Americas. To identify what is different requires a better understanding of the underlying immunological substrate of the population, and how these factors affect susceptibility to infection, progression of symptoms, transmission, and responses to SARS-CoV-2 vaccination.

Study objectives

1. Determine the risk and predictors of infection and disease among contacts of SARS-CoV-2 infection subjects in Malawi
2. Determine whether innate immune responses lower the risk of SARS-CoV-2 infection and disease, and acquisition and duration of vaccine responses.
3. Assess whether alterations in innate immune responses relevant to SARS-CoV-2 are associated with malaria or intestinal parasite infections.
4. Assess the acquisition and longevity of antibodies (Ab) and cellular adaptive responses elicited by SARS-CoV-2 infection and vaccination.
5. Assess whether malaria and intestinal parasite infections, chronic/mild undernutrition, and anemia mediate alterations in Ab and other adaptive cellular responses to SARS-CoV-2 through innate immune responses or a different unknown mechanism.

The investigators hypothesize that malaria and intestinal parasitic diseases may result in enhanced or tolerogenic innate immune responses that decrease the risk of symptomatic COVID-19. On the other hand, these conditions and deficiency of micronutrients may decrease the acquisition and longevity of antibodies induced by natural infection and SARS-CoV-2 vaccines, increasing the risk of re-infection and breakthrough infections to vaccination.

To test these hypotheses, up to 200 symptomatic individuals (index cases)will be enrolled, their household contacts (anticipated ~700), and up to 600 vaccinees. The specific innate immune phenotypes that differentiate uninfected Malawians from Western controls (based on samples from blood banks) and whether those responses are protecting Malawians from infection and/or progression of disease will be assessed. Infected participants and vaccinees will be followed for up to 1.5 years to assess acquisition and longevity of Ab responses and memory B cells.

Inclusion Criteria Index Cases

1. Presents with symptoms of COVID-19 and has infection confirmed through RT-PCR or a rapid antigen test;
2. Aged 5 years to 75 years and plans to live in Blantyre, in the catchment area of the target research health centers for the following 6 months;
3. Confirmed SARS-CoV-2 infection and share a household with 1 or more individuals of eligible age;
4. Has not received a SARS-CoV-2 vaccine in the previous 3 months
5. Willingness to comply with study procedures and visits, and provides informed consent.

Household Contacts of the Confirmed SARS-CoV-2 Case

1. Aged 5 years to 75 years and plans to live in Blantyre, in the catchment area of the target research health centers in the following 6 months;
2. Willingness to comply with study procedures and follow-up visits and provides informed consent.
3. Has not received a SARS-CoV-2 vaccine in the previous 3 months

Vaccinees

1) Aged 18 years to 75 years; 2) Willingness to receive the primary regimen of the AZ and/or JJ vaccines 2) Not in the other 2 cohorts; 4) Willingness to comply with study procedures and follow-up visits and provides informed consent.

5) Has not received a prior dose of a SARS-CoV-2 vaccine

Exclusion Criteria Index Cases

1. Conditions that precludes from adherence to the visit schedule;
2. 50% or more of household members decline to participate.
3. Pregnancy at the enrollment visit
4. Long term use of cotrimoxazole prophylaxis

Household Contacts of the Confirmed SARS-CoV-2 Case

1. Conditions that preclude adherence to the visit schedule.
2. Participants with 2 consecutive negative SARS-CoV-2 RT-PCRs will be excluded from visits after M1.
3. Pregnancy at the enrollment visit
4. Long term use of cotrimoxazole prophylaxis

Vaccinees

1. Conditions that preclude adherence to the visit schedule.
2. Pregnancy at the enrollment visit
3. Long term use of cotrimoxazole prophylaxis

This study will take place in Blantyre, in one or all of the following health centers and their catchment areas: Bangwe, Chileka, Chilomoni, and Mpemba. These health centers were chosen because transmission of SARS-CoV-2 and malaria were recorded in their catchment area in the past two years. If needed, to reach the recruitment target, different health services in Blantyre may be considered for this research.