Combination Assessment Trial of COVID-19 Vaccines (COMBAT-COVID) (COMBAT-COVID)

Immunogenicity and Safety of Heterologous Combinations of COVID-19 Vaccines Available Under Emergency Use Authorization in Pakistan: A Randomized Phase II Trial

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.

Study Overview

• Status: Not yet recruiting
• Conditions: COVID 19 Vaccine
• Intervention / Treatment: Biological: BIBP (CNBG, Sinopharm) WIV; Biological: CanSinoBIO; Biological: AstraZeneca ChAdOx

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 1680
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Farah Qamar; Phone Number: 02134865035; Email: farah.qamar@aku.edu
• Study Contact Backup: Name: Tahir Yousafzai; Phone Number: 02134864031; Email: tahir.yousafzai@aku.edu

Study Locations

• Pakistan
  • Punjab
    • Islamabad, Punjab, Pakistan
      • National Institute Of Health
      • Contact: Omera Naseer; Email: omera_shuaib@hotmail.com
    • Lahore, Punjab, Pakistan
      • Chughtai Lab
      • Contact: Shazia Sultana; Phone Number: 03332122381; Email: shazia.sultana@aku.edu
  • Sindh
    • Karachi, Sindh, Pakistan
      • Aga Khan University
      • Contact: Rakshanda Ambreen; Phone Number: 03322290106

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

9

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Heterologous 1; BIBP (CNBG, Sinopharm) WIV (0.5ml) at baseline CanSinoBIO (0.5ml) after 70±7 days (10 wks±2) (160 participants)	Biological: BIBP (CNBG, Sinopharm) WIV; BIBP (CNBG, Sinopharm) WIV (Whole Inactivated Virus in a single dose, prefilled syringe with a storage temperature of 2-8°C); Biological: CanSinoBIO; CanSinoBIO (Viral Vector in a single dose, prefilled syringe with a storage temperature of 2-8°C)
Active Comparator: Heterologous 2; BIBP (CNBG, Sinopharm) WIV (0.5ml) at baseline AstraZeneca ChAdOx (0.5ml) after 70±7 days (10 wks±2) (160 participants)	Biological: BIBP (CNBG, Sinopharm) WIV; BIBP (CNBG, Sinopharm) WIV (Whole Inactivated Virus in a single dose, prefilled syringe with a storage temperature of 2-8°C); Biological: AstraZeneca ChAdOx; AstraZeneca ChAdOx (Viral Vector in a multi-dose vial consisting of 10 doses with a storage temperature of 2-8°C)
Active Comparator: Heterologous 3; CanSinoBIO (0.5ml) at baseline BIBP (CNBG, Sinopharm) WIV (0.5ml) after 70±7 days (10 wks±2) (160 participants)	Biological: BIBP (CNBG, Sinopharm) WIV; BIBP (CNBG, Sinopharm) WIV (Whole Inactivated Virus in a single dose, prefilled syringe with a storage temperature of 2-8°C); Biological: CanSinoBIO; CanSinoBIO (Viral Vector in a single dose, prefilled syringe with a storage temperature of 2-8°C)
Active Comparator: Heterologous 4; CanSinoBIO (0.5ml) at baseline AstraZeneca ChAdOx (0.5ml) after 70±7 days (10 wks±2) (160 participants)	Biological: CanSinoBIO; CanSinoBIO (Viral Vector in a single dose, prefilled syringe with a storage temperature of 2-8°C); Biological: AstraZeneca ChAdOx; AstraZeneca ChAdOx (Viral Vector in a multi-dose vial consisting of 10 doses with a storage temperature of 2-8°C)
Active Comparator: Heterologous 5; AstraZeneca ChAdOx (0.5ml) at baseline BIBP (CNBG, Sinopharm) WIV(0.5ml) after 70±7 days (10 wks±2) (160 participants)	Biological: BIBP (CNBG, Sinopharm) WIV; BIBP (CNBG, Sinopharm) WIV (Whole Inactivated Virus in a single dose, prefilled syringe with a storage temperature of 2-8°C); Biological: AstraZeneca ChAdOx; AstraZeneca ChAdOx (Viral Vector in a multi-dose vial consisting of 10 doses with a storage temperature of 2-8°C)
Active Comparator: Heterologous 6; AstraZeneca ChAdOx (0.5ml) at baseline CanSinoBIO (0.5ml) after 70±7 days (10 wks±2) (160 participants)	Biological: CanSinoBIO; CanSinoBIO (Viral Vector in a single dose, prefilled syringe with a storage temperature of 2-8°C); Biological: AstraZeneca ChAdOx; AstraZeneca ChAdOx (Viral Vector in a multi-dose vial consisting of 10 doses with a storage temperature of 2-8°C)
Active Comparator: Homologous 7; BIBP (CNBG, Sinopharm) WIV (0.5ml) at baseline BIBP (CNBG, Sinopharm) WIV (0.5ml) after 70±7 days (10 wks±2) Full dose booster: 80 participants (0.5ml) 6 months after second dose Fractional dose booster: 80 participants (dose to be decided) 6 months after second dose No booster: 80 participants (240 participants)	Biological: BIBP (CNBG, Sinopharm) WIV; BIBP (CNBG, Sinopharm) WIV (Whole Inactivated Virus in a single dose, prefilled syringe with a storage temperature of 2-8°C)
Active Comparator: Homologous 8; CanSinoBIO (0.5ml) at baseline CanSinoBIO (0.5ml) after 70±7 days (10 wks±2) Full dose booster: 80 participants (0.5ml) 6 months after second dose Fractional dose booster: 80 participants (dose to be decided) 6 months after second dose No booster: 80 participants (240 participants)	Biological: CanSinoBIO; CanSinoBIO (Viral Vector in a single dose, prefilled syringe with a storage temperature of 2-8°C)
Active Comparator: Homologous 9; AstraZeneca ChAdOx (0.5ml) at baseline AstraZeneca ChAdOx (0.5ml) after 70±7 days (10 wks±2) Full dose booster: 80 participants (0.5ml) 6 months after second dose Fractional dose booster: 80 participants (dose to be decided) 6 months after second dose No booster: 80 participants (240 participants)	Biological: AstraZeneca ChAdOx; AstraZeneca ChAdOx (Viral Vector in a multi-dose vial consisting of 10 doses with a storage temperature of 2-8°C)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Primary Endpoint	Anti-spike IgG antibodies by ELISA will be measured in serum	At weeks 14 and 38

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Secondary Endpoint 1a	Serious adverse events (SAE) and adverse events of special interest (AESI) assessed through phone calls using a structured questionnaire	Through study completion, an average of 2 and a half years
Secondary Endpoint 1b	Solicited local and systemic reactions assessed through phone calls using a structured questionnaire	Within 7 days post each dose
Secondary Endpoint 1c	Unsolicited adverse reactions assessed through phone calls using a structured questionnaire	Within 28 days post each dose
Secondary Endpoint 1d	Medically attended adverse reactions assessed through phone calls using a structured questionnaire	Up to 3 months post booster dose
Secondary Endpoint 1e:1	Detect changes in urea levels in serum Unit of measurement: mg/dL	From baseline to 4 weeks post each dose
Secondary Endpoint 1e:2	Detect changes in sodium levels in serum Unit of measurement: mEq/L	From baseline to 4 weeks post each dose
Secondary Endpoint 1e:3	Detect changes in potassium levels in serum Unit of measurement: mEq/L	From baseline to 4 weeks post each dose
Secondary Endpoint 1e:4	Detect changes in creatinine levels in serum Unit of measurement: mg/dL	From baseline to 4 weeks post each dose
Secondary Endpoint 1e:5	Detect changes in bilirubin levels in serum Unit of measurement: mg/dL	From baseline to 4 weeks post each dose
Secondary Endpoint 1e:6	Detect changes in Alanine Aminotransferase (ALT) levels in serum Unit of measurement: IU/L	From baseline to 4 weeks post each dose
Secondary Endpoint 1e:7	Detect changes in ALT-phosphatase levels in serum Unit of measurement: IU/L	From baseline to 4 weeks post each dose
Secondary Endpoint 1e:8	Detect changes in albumin levels in serum Unit of measurement: g/dL	From baseline to 4 weeks post each dose
Secondary Endpoint 1e:9	Detect changes in Aspartate Aminotransferase (AST) levels in serum Unit of measurement: units/L	From baseline to 4 weeks post each dose
Secondary Endpoint 1e:10	Detect changes in blood hematology tests through complete blood count (CBC) using whole blood	From baseline to 4 weeks post each dose
Secondary Endpoint 2	Neutralizing antibody response (pseudo-virus neutralization assay) against SARS-CoV-2 in serum	At day 0, and weeks 4, 14, 24, 28, 48, 60 and 96 as per schedule of events (only immunology cohort) and at baseline and 4 weeks post booster dose in general cohort
Secondary Endpoint 3a	Anti-spike IgG responses measured by ELISA will be measured in serum	Measured at Day 0, and Weeks 4, 10, 14, 24, 28, 48, 60 and 96 as per schedule of events (in full cohort)
Secondary Endpoint 3b	Anti-nucleocapsid IgG will be measured in serum	Measured at Day 0, and Week 2, 14, 24, 48, 60, and 96 as per schedule of events (in full cohort)
Secondary Endpoint 3c	ELISpot assays will be performed using peripheral blood mononuclear cells polymorphonuclear cells (PBMC)	At Day 0, and week 2, 4, 10, 12, 14, 24, 48, 96 (immunology cohort)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory Endpoint 1a	Neutralizing antibody response (pseudo-virus neutralization assay) against SARS-CoV-2 and anti-spike IgG responses measured by ELISA in serum	Within 1 week of breakthrough infection among the participants
Exploratory Endpoint 1b	Sequencing of SARS-CoV-2 viruses of breakthrough infections in vaccine recipients by extracting DNA from nasal swabs	Througout the study
Exploratory Endpoint 1c	NNeutralizing antibody response (pseudo-virus neutralization assay) against SARS-CoV-2 VOCs circulating in Pakistan in serum through ELISAVOCs circulating in Pakistan	Througout the study
Exploratory Endpoint 1d	Intracellular cytokine staining (ICS) will be performed to assess the phenotypic characteristics of CD4 and CD8 T cells recognizing the antigen by high throughput multicolor flow cytometry by extracting peripheral blood mononuclear cells (PBMC)	Througout the study
Exploratory Endpoint 1e	Strategic stage-gated Systems Serology analysis using Luminex in serum samples	Througout the study

Collaborators and Investigators

• Sponsor: Aga Khan University Hospital, Pakistan
• Collaborators: Harvard Medical School (HMS and HSDM); University of Oxford; International Vaccine Institute; Coalition for Epidemic Preparedness Innovations; Chughtai Lab; National Institute of Health, Pakistan
• Investigators: Principal Investigator: Farah Qamar, Aga Khan University Hospital, Pakistan (AKU); Study Director: Tahir Yousafzai, Aga Khan University Hospital, Pakistan (AKU); Study Director: Zahra Hassan, Aga Khan University Hospital, Pakistan (AKU); Study Director: Junaid Iqbal, Aga Khan University Hospital, Pakistan (AKU); Study Director: Kiran Iqbal, Aga Khan University Hospital, Pakistan (AKU); Study Director: Sonia Qureshi, Aga Khan University Hospital, Pakistan (AKU); Study Director: Maria Fletcher, Aga Khan University Hospital, Pakistan (AKU); Study Director: Najeeha Iqbal, Aga Khan University Hospital, Pakistan (AKU); Study Director: Momin Kazi, Aga Khan University Hospital, Pakistan (AKU); Study Director: Shazia Sultana, Aga Khan University Hospital, Pakistan (AKU); Study Director: Andrew Pollard, University of Oxford; Study Director: Matthew Snape, University of Oxford; Study Director: Teresa Lambe, University of Oxford; Study Director: Xinxue Liu, University of Oxford; Study Director: Anh Wartel, International Vaccine Institute (IVI), Korea; Study Director: Jean-Louis Excler, International Vaccine Institute (IVI), Korea; Study Director: Deok-Ryun Kim, International Vaccine Institute (IVI), Korea; Study Director: Galit Alter, Ragon Institute, Harvard School of Medicine, USA; Study Director: Aamir Ikram, National Institute of Health (NIH) Pakistan; Study Director: Ghazala Parveen, National Institute of Health (NIH) Pakistan; Study Director: Firdous Nawaz Khan, National Institute of Health (NIH) Pakistan; Study Director: Omera Naseer, National Institute of Health (NIH) Pakistan

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• Saleem AF, Yousafzai MT, Mach O, Khan A, Quadri F, Weldon WC, Oberste MS, Zaidi SS, Alam MM, Sutter RW, Zaidi AKM. Evaluation of vaccine derived poliovirus type 2 outbreak response options: A randomized controlled trial, Karachi, Pakistan. Vaccine. 2018 Mar 20;36(13):1766-1771. doi: 10.1016/j.vaccine.2018.02.051. Epub 2018 Feb 21.
• Yousafzai MT, Saleem AF, Mach O, Baig A, Sutter RW, Zaidi AKM. Feasibility of conducting intradermal vaccination campaign with inactivated poliovirus vaccine using Tropis intradermal needle free injection system, Karachi, Pakistan. Heliyon. 2017 Sep 18;3(8):e00395. doi: 10.1016/j.heliyon.2017.e00395. eCollection 2017 Aug.
• Saleem AF, Mach O, Yousafzai MT, Kazi Z, Baig A, Sajid M, Jeyaseelan V, Sutter RW, Zaidi AKM. One-Year Decline of Poliovirus Antibodies Following Fractional-Dose Inactivated Poliovirus Vaccine. J Infect Dis. 2021 Apr 8;223(7):1214-1221. doi: 10.1093/infdis/jiaa504.
• Riaz A, Mohiuddin S, Husain S, Yousafzai MT, Sajid M, Kabir F, Rehman NU, Mirza W, Salam B, Nadeem N, Pardhan K, Khan KMA, Raza SJ, Arif F, Iqbal K, Zuberi HK, Whitney CG, Omer SB, Zaidi AKM, Ali A; Pakistan Pneumococcal Vaccine Study Group. Effectiveness of 10-valent pneumococcal conjugate vaccine against vaccine-type invasive pneumococcal disease in Pakistan. Int J Infect Dis. 2019 Mar;80:28-33. doi: 10.1016/j.ijid.2018.12.007. Epub 2018 Dec 18.
• Qamar FN, Batool R, Qureshi S, Ali M, Sadaf T, Mehmood J, Iqbal K, Sultan A, Duff N, Yousafzai MT. Strategies to Improve Coverage of Typhoid Conjugate Vaccine (TCV) Immunization Campaign in Karachi, Pakistan. Vaccines (Basel). 2020 Nov 19;8(4):697. doi: 10.3390/vaccines8040697.

Helpful Links

• Patel D. Poverty in Pakistan: Numerous efforts, many numbers, not enough results 2015
• Pakistan Cases Details-Government of Pakistan 2021

Study record dates

Study Major Dates

• Study Start (Anticipated): March 1, 2022
• Primary Completion (Anticipated): June 30, 2024
• Study Completion (Anticipated): June 30, 2024

Study Registration Dates

• First Submitted: December 13, 2021
• First Submitted That Met QC Criteria: December 16, 2021
• First Posted (Actual): December 17, 2021

Study Record Updates

• Last Update Posted (Actual): February 18, 2022
• Last Update Submitted That Met QC Criteria: February 17, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: 6739

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes