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NCT Number: NCT05973084

COVID-19 Transmission and Morbidity in Malawi

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.

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Key information

Conditions

SARS CoV 2 Infection COVID-19 Coronaviridae Infections Coronavirus Infections Infections Lung Diseases Nidovirales Infections Pneumonia Pneumonia, Viral RNA Virus Infections Respiratory Tract Diseases Respiratory Tract Infections SARS CoV 2 Vaccination Virus Diseases

Age range

5 year–75 year

Sex eligibility

All sexes

Study type

Observational

Primary location

Health center, Blantyre, Malawi

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

Index Cases

  • Presents with symptoms of COVID-19 and has infection confirmed through RT-PCR or a rapid antigen test;
  • 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;
  • Confirmed SARS-CoV-2 infection and share a household with 1 or more individuals of eligible age;
  • Has not received a SARS-CoV-2 vaccine in the previous 3 months
  • Willingness to comply with study procedures and visits, and provides informed consent.

Household Contacts of the Confirmed SARS-CoV-2 Case

  • 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;
  • Willingness to comply with study procedures and follow-up visits and provides informed consent.
  • Has not received a SARS-CoV-2 vaccine in the previous 3 months

Vaccinees

  • 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.
  • Has not received a prior dose of a SARS-CoV-2 vaccine

Exclusion criteria

Index Cases

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

Household Contacts of the Confirmed SARS-CoV-2 Case

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

Vaccinees

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

Treatment and study plan

Primary outcomes

  1. Risk of asymptomatic infection among contacts who acquire infection

    Time frame: up to 2 weeks

    Proportion of household members who acquire an asymptomatic (vs. symptomatic) infection among household contacts of an index case

  2. Duration of neutralizing antibody (NAb) responses against two viruses

    Time frame: up to 15 months

    Among participants who develop neutralizing antibody responses, days to decay antibody levels to a 25% level from baseline. NAbs levels, defined as dilution of serum or plasma required to inhibit 50% of virus entry into a target cell lines (ID50) will be measured against the vaccine matched viruses and an additional predominant circulating variant of concern at the time participant samples are collected.

  3. Change in frequencies of classical (CD14+CD16-) monocytes and markers of activation/inflammation with and without stimulation by by toll like receptor (TLR) and retinoic acid-inducible gene I (RIG-I) like receptors (RLR) ligands

    Time frame: baseline, 2 weeks

    Difference between measures obtained at 2 weeks and baseline in percentage positive. Percentage positive can range from 0 to 100. Change = Percentage positive at 2 weeks - Percentage positive at baseline

Secondary outcomes

  1. Probably of infections in a household

    Time frame: up to 2 weeks

    Estimated probability of infection among household contacts of an index case

  2. Duration of COVID-19 symptoms, reinfection rates, and breakthrough infection rates

    Time frame: up to 15 months

    Days to resolve symptoms in each symptomatic episode and number of confirmed SARS-CoV-2 infection through RT-PCR after a first infection or vaccination

  3. Change in activation status of monocytes and monocyte-derived macrophages (MDMs) with and without stimulation with TLR and RLR agonists in vitro

    Time frame: baseline, 2 weeks

    Percentage positive of activation markers (CD169, CD86, and CD80) will be quantified by flow cytometry and can range from 0 to 100 of percent positive cells. Change = Percentage positive of CD169, CD86, and CD80 at 2 weeks - Percentage positive at baseline

  4. Change in cell activation markers among stimulated and unstimulated classical monocytes and MDMs

    Time frame: baseline, 2 weeks

    Difference between measures obtained at 2 weeks and baseline in percentage positive of CD169, CD86 and CD80 expression will be measured quantified through flow cytometry. Change = Percentage positive of CD169, CD86, and CD80 at 2 weeks - Percentage positive at baseline

  5. Change in concentrations of pro-inflammatory cytokines and chemokines produced by classic monocytes and MDMs

    Time frame: baseline, 2 weeks

    Difference between measures obtained at 2 weeks and baseline in concentration (median fluorescence intensity (MFI)) from M0 to M2 of chemokines and cytokines (e.g., MCP-1, IFNα, IFNβ, IFNλ, IP-10, IL-6, and IL-1 β) quantified through Luminex-based assays

  6. Change in expression of 770 host response genes in classical monocytes and MDMs

    Time frame: baseline, 2 weeks

    Host gene expression will be quantitated through NanoString nCounter Infectious Disease Host Response Panel, focusing on Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Interferon regulatory factor 3 (IRF3)-controlled dependent transcripts. Changes in gene expression will be reported as fold increase at 2 weeks over that observed at baseline

  7. Antibody magnitude to 3 SARS-COV-2 antigens and 3 trimers

    Time frame: up to 12 months and 18 months, depending on the cohort

    Concentration (in Optical Density) of Immunoglobulin G (IgG) against Spike (S) protein, Receptor binding domain (RBD), and Nucleocapsid based trimer (N trimers) based on the vaccine matched variant and two other circulating variants of concern will be measured by Enzyme Linked Immunosorbent Assay (ELISA))

  8. NAb responses measured against 3 viruses and through a surrogate assay (sENAB)

    Time frame: up to 12 months, 15 months

    Inhibition of binding by RBD to ACE2 (ID50) receptor by plasma antibodies using a plate based surrogate neutralization assay.

  9. Fc-gamma receptors (FcγR) -II/III binding functional antibody activities

    Time frame: 1 month

    Binding activity (in Optical Density) of FcγR against S, RBD antigens based measured by plate-based assay

  10. Duration of antibody-dependent cellular cytotoxicity (ADCC) responses

    Time frame: up to 12 months

    Using fresh Natural Killer (NK) cells that were incubated with interleukin 2 (IL-2), the investigators will quantify CD107a expression (determined by flow cytometry) by Natural Killer cells after incubation with opsonized antigen-coated beads (S antigen). Percentage of NK cells positive for CD107a

  11. Magnitude of dimeric Immunoglobulin A (dIgA)

    Time frame: 1 month

    Binding activity (in Optical Density) of IgA against S, RBD antigens based measured by ELISA.

  12. Frequencies of B (S-antigen specific and total) and plasma cells, and innate immunity parameters

    Time frame: up to 12 months, 15 months

    Proportion of B cells (S-antigen and total) and plasma cells as a percentage of total B cells and total lymphocytes and innate immune parameters as a percentage of total immune cells at 12 and 15 months. Possible units can range from 0 to 16. Proportions will be compared between different patient groups, for example percentage positive in malaria uninfected compared to percentage positive in malaria infected patients.

Study contacts

Contact information is provided by the study sponsor or research team.

Aditi S Kothari, BDS MDSc MPH

CONTACT

[email protected]

(617) 358-2441

Clarissa Valim, MD ScD

CONTACT

[email protected]

(617) 414-1260

Sponsors and collaborators

Lead sponsor

Boston University

Other

Collaborators

  • Burnet Institute
  • Kamuzu University of Health Sciences
  • National Institute of Allergy and Infectious Diseases (NIAID)

Registry information

Acronym: COVID-TMM

Important dates

Study start
2023
Primary completion
2028
Study completion
2028
First posted
Aug 2, 2023
Registry last updated
May 28, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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