Since the emergence of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogen in late 2019, millions of people around the world have fallen ill and died from coronavirus disease 2019 (COVID-19), with variant-fueled case spikes causing repeated cycles of morbidity and mortality. The rapid development and emergency use authorization of vaccines against SARS-CoV-2 presents an enormous opportunity to protect populations, but bottlenecks in production have led to demand for vaccines that far outpaces supply. This project will investigate the immunogenicity of fractional doses of SARS-CoV-2 vaccines given a minimum of six months following an initial two-dose schedule or following natural immunity via documented infection. The consortium of research partners from the Sabin Vaccine Institute, Aga Khan University, Fundação Oswaldo Cruz (Fiocruz), and Stanford University will recruit volunteers to receive a full or fractional booster dose of BNT162b2, AZD1222 or Sinovac following receipt of their primary vaccination series or PCR-confirmed natural infection in Pakistan. The research team will follow participants for six months from boosting, with blood draws at baseline, 28 days, 3 months and 6 months, and measure sero-response rate (SRR) by anti-Spike immunoglobulin G (IgG) binding enzyme-linked immunosorbent assay (ELISA) with the ultimate aim of identifying whether fractional doses provide a similar immune response compared to full doses of vaccine.

Inclusion Criteria:

• Healthy male or female individuals aged 18 years to 60 years
• Participant is willing and able to give written informed consent for participation in the trial
• Individuals who can comply with trial procedures and are available for the duration of follow-up.

Brazil:

● Previous vaccination with a complete primary series of Sinovac (Priming Group 1), AZD1222 (Priming Group 2), or BNT162b2 (Priming Group 3-B) at least 6 months prior to screening

Pakistan:

● Previous vaccination with a complete primary series of Sinovac (Priming Group 1) or AZD1222 (Priming Group 2) at least 6 months prior to screening, or PCR-confirmed natural infection (Priming Group 3-P) between February 2021 - 6 months prior to screening

Exclusion Criteria:

• Has a contraindication to BNT162b2, AZD1222 or Sinovac
• Has received an incomplete primary COVID-19 vaccination series
• Has received 3 doses of COVID-19 vaccine
• Has received heterologous primary COVID-19 vaccination series
• History of a solid organ or bone marrow transplant
• History of malignancy (other than non-melanoma skin cancer) within the past five years
• Currently on hemodialysis
• Any confirmed or suspected immunosuppressive or immunodeficiency condition or diagnosis
• On chronic (>30 days) use of immunosuppressive medications at the time of enrollment (except topical steroids or short-term oral steroids, i.e., ≤14 days)
• Known diagnosis of HIV with CD4 count <200 cells/mm3 (in the past 6 months)
• Active or history of previous auto-immune neurological disorders (e.g., multiple sclerosis, Guillain-Barre syndrome, transverse myelitis) (excluding Bell's palsy)
• Has received anti-CD20 monoclonal antibodies for any reason in the past 12 months
• Has received monoclonal antibodies to treat a previous COVID-19 event
• Pregnant at screening
• Positive SARS-CoV-2 Antigen test in respiratory specimen at screening
• Planning to migrate out of the study area within 6 months of the enrollment
• Participants currently enrolled in any other COVID-19 vaccine research trial in which they are getting a COVID-19 vaccine during the study period
• Illiterate individuals (Brazil only)
• Has a severe and/or uncontrolled comorbidity

Pakistan (natural infection Priming Group (Priming Group 3-P)):

● Prior vaccination with ANY vaccine against COVID-19

The study will be observer-blind. Participants, data collectors (e.g., Investigator), and data evaluators (e.g., trial statisticians) are blinded. Only the staff involved in vaccine delivery will be unblinded and aware of which vaccine the participant is receiving (group allocation). Study staff who collect information on symptoms and adverse events, laboratory staff and statisticians conducting the analysis will all be blinded to the vaccine and dosage received.