This is a randomized, phase II trial which will be conducted among volunteers aged 18 years and above in Karachi, Lahore and Islamabad, Pakistan. The trial will have nine arms and is an open label study. Trained persons will administer the vaccine and draw blood under strict aseptic measures. The immune responses using pseudo neutralizing antibodies against SARS-CoV-2 in COVID-19 seronegative participants receiving heterologous and homologous COVID-19 vaccines will be assessed. Anti-spike IgG antibodies by ELISA and pseudo neutralizing antibodies against SARS-CoV-2 will also be measured. The safety and reactogenicity will also be assessed by recording serious adverse events (SAE), adverse events of special interest (AESI), solicited local and systemic reactions and medically attended adverse reactions through biochemical and hematological tests or safety measures throughout the study. In most cases the adverse events are mild and self-limiting but can require medication and/or hospitalization in rare cases. Participants suffering from any adverse event causally related to the to the trial intervention will be facilitated and the cost of treatment including laboratory investigations will be provided to them. Data confidentiality will be ensured by delinking names in forms and through password protection.

This is a randomized, phase II trial which will be conducted among volunteers aged 18 years and above in Karachi, Lahore and Islamabad, Pakistan. The investigators will be assessing the safety and reactogenicity of heterologous and homologous COVID-19 vaccines and characterize the immune responses using pseudo neutralizing antibodies against SARS-CoV-2 in COVID seronegative participants immunized with heterologous and homologous COVID-19 vaccines regimens. This approach will allow combination of different vaccines in case the same vaccine is not available at the time of boosting (follow-up dose) and will help mitigate the shortage of available COVID-19 vaccines. Furthermore, the combination strategy might prove to be more effective against the variants of concern of SARS CoV-2.

The total duration of the trial will be approximately 2 ½ years. The study will enroll participants which will be divided into 2 cohorts, one for a more detailed immunological assessment and one for main immunology endpoints. The study will include 9 study groups with different combinations of COVID-19 vaccine schedule (6 heterologous combinations and 3 homologous combinations plus booster in homologous arms). The investigators will be measuring Anti-spike IgG antibodies by ELISA at week 14 (4 weeks post booster dose) and pseudo neutralizing antibodies against SARS-CoV-2 at day 0, and weeks 4, 14, 24, 28, 48, 60 and 96 as per schedule of events for the immunology cohort and at baseline and 4 weeks post second dose in general cohort. This is a pragmatic trial where the interval between the two doses will be kept longer than the conventional recommendations of 21/28 days. Additionally, the investigators will also be assessing safety and reactogenicity by recording serious adverse events (SAE), adverse events of special interest (AESI), solicited local and systemic reactions within 7 days post each dose, unsolicited reactions within 28 days post each dose, medically attended adverse reactions up to 3 months post booster dose and changes from baseline to 4 weeks post each dose in biochemical and hematological tests or safety measures throughout the study.

A trained person will administer the vaccine and draw blood samples under strict aseptic techniques to ensure minimum discomfort and reduce the risk of infection. There is a risk of adverse events associated with all vaccines and there can be some risks associated with vaccine administration and blood collection procedures like pain, redness, itch, swelling, fever, feverishness, chills, joint pains, muscle pains, fatigue, headache, malaise, nausea, vomiting, diarrhea etc. However, in most cases the adverse events are mild and self-limiting but can require medication and/or hospitalization in rare cases. Participants suffering from any adverse event causally related to the to the trial intervention will be facilitated and the cost of treatment including laboratory investigations will be provided to them. The participants will also be compensated for their time, the inconvenience of getting jabs and providing blood samples.

Confidentiality of all the data collected from the population is a top priority. All the names and personal information regarding any individual will not to be disclosed separately. The data will be published collectively. All the names present in the forms will be de linked and forms will be coded accordingly all the data files will be password protected. Data that will be shared with University of Oxford, International Vaccine Institute (IVI), Seoul, Republic of Korea, Ragon Institute, Harvard School of Medicine, USA, National Institute of Health (NIH) Pakistan will have multi-layered security with several layers of encryption to protect data. Blood samples from patients enrolled will be stored at our research office in Infectious disease research laboratory at Aga Khan University Karachi, labelled with identification numbers not participant name. During the storage, only dedicated members of our study team will have access to the samples. De-identified research data maybe be stored indefinitely. If volunteers consent to be contacted for future research, a record of this consent will be recorded, retained, and stored securely and separately from the research data. If volunteers consent to have their samples stored and used for future research, information about their consent form will be retained and stored securely as per Biobanking procedures and SOPs. Identifiable information such as contact details will be stored for a minimum of 5 years from the end of the study. This includes storage of consent forms. Storage of data will be reviewed every 5 years and files will be confidentially destroyed if storage is no longer required. During the storage, only the local PIs and researchers designated by them will have access to the data or samples.

Inclusion Criteria:

- Adult male and female volunteers aged 18 years and above and volunteers with well controlled mild or moderate comorbidities will be enrolled to participate in trial.

• Participant is willing and able to give written informed consent for participation in the trial.
• Male or Female aged 18 years or above and in good health as determined by a trial clinician. Participants may have well controlled mild-moderate comorbidity.
• In the Investigator's opinion, is able and willing to comply with all trial requirements.
• Residing in the study areas.

Exclusion Criteria:

The participant may not enter in the trial if ANY of the following apply:

• Pregnant women or those who are planning to conceive within next 70 days.
• Women who are breast feeding
• Already received any COVID-19 vaccine or any other vaccine likely to impact on interpretation of the trial data (e.g., Adenovirus vectored vaccines).
• Administration of immunoglobulins and/or any blood products within the three months preceding the planned administration of the vaccines.
• Any confirmed or suspected immunosuppressive or immunodeficient state; asplenia; recurrent severe infections and use of immunosuppressant medication within the past 6 months, except topical steroids or short-term oral steroids (course lasting ≤14 days)
• History of allergic disease or reactions likely to be exacerbated by any component of study vaccines (e.g., hypersensitivity to the active substance of the COVID-19 vaccines included in the study groups
• Any history of anaphylaxis.
• Current diagnosis of or treatment for cancer (except basal cell carcinoma of the skin and cervical carcinoma in situ)
• Bleeding disorder (e.g., factor deficiency, coagulopathy, or platelet disorder), or prior history of thrombotic events and/or significant bleeding or bruising following IM injections or venipuncture.
• Continuous use of anticoagulants, such as coumarins and related anticoagulants (i.e., warfarin)
• Any other significant disease, disorder or finding which may significantly increase the risk to the volunteer because of participation in the study, affect the ability of the volunteer to participate in the study or impair interpretation of the study data.
• Severe and/or uncontrolled cardiovascular disease, respiratory disease, gastrointestinal disease, liver disease, renal disease, endocrine disorder, and neurological illness (mild/moderate well controlled comorbidities are allowed)
• History of active or previous auto-immune neurological disorders (e.g., multiple sclerosis, Guillain-Barre syndrome, transverse myelitis). Bell's palsy will not be an exclusion criterion.
• History of laboratory confirmed COVID-19 within 6 months prior to enrolment (history of SARS-CoV-2 detection by PCR or antibody to SARS-CoV-2).
• Scheduled elective surgery during the trial.
• Participants enrolled in any other research trial.
• Participants planning to migrate out of the study area within 2 years of the study.

Temporary Exclusion Criteria:

If the volunteer has any of the following, they will not be enrolled that day.

• Acute respiratory illness (moderate or severe illness with or without fever)
• Fever (temperature greater than 38°C) They may be considered for enrolment later in the trial if they recover in sufficient time.