COVID-19 Transmission and Morbidity in Malawi
- Conditions
- SARS CoV 2 VaccinationSARS CoV 2 Infection
- Registration Number
- NCT05973084
- Lead Sponsor
- Boston University
- Brief Summary
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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 1500
Not provided
Not provided
Study & Design
- Study Type
- OBSERVATIONAL
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method 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 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
Risk of asymptomatic infection among contacts who acquire infection up to 2 weeks Proportion of household members who acquire an asymptomatic (vs. symptomatic) infection among household contacts of an index case
Duration of neutralizing antibody (NAb) responses against two viruses 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.
- Secondary Outcome Measures
Name Time Method Duration of COVID-19 symptoms, reinfection rates, and breakthrough infection rates 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
Change in concentrations of pro-inflammatory cytokines and chemokines produced by classic monocytes and MDMs 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
Antibody magnitude to 3 SARS-COV-2 antigens and 3 trimers 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))
Change in expression of 770 host response genes in classical monocytes and MDMs 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
Fc-gamma receptors (FcγR) -II/III binding functional antibody activities 1 month Binding activity (in Optical Density) of FcγR against S, RBD antigens based measured by plate-based assay
Magnitude of dimeric Immunoglobulin A (dIgA) 1 month Binding activity (in Optical Density) of IgA against S, RBD antigens based measured by ELISA.
Frequencies of B (S-antigen specific and total) and plasma cells, and innate immunity parameters 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.
Change in cell activation markers among stimulated and unstimulated classical monocytes and MDMs 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
Probably of infections in a household up to 2 weeks Estimated probability of infection among household contacts of an index case
Change in activation status of monocytes and monocyte-derived macrophages (MDMs) with and without stimulation with TLR and RLR agonists in vitro 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
NAb responses measured against 3 viruses and through a surrogate assay (sENAB) 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.
Duration of antibody-dependent cellular cytotoxicity (ADCC) responses 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
Trial Locations
- Locations (2)
Health center
🇲🇼Blantyre, Malawi
BU School of Public Health, Global Health Department
🇺🇸Boston, Massachusetts, United States