Sisonke (Together): OPEN LABEL TRIAL COVID-19

Purpose To monitor the effectiveness of the single dose Ad26.COV2.S COVID-19 vaccine among health care workers (HCW) as compared to the general unvaccinated population in South Africa

Study design Open-label, single-arm phase 3B vaccine implementation study

Rationale South Africa is severely affected by the global COVID-19 epidemic, but currently no vaccine has been rolled out. The recent promising results of the 'ENSEMBLE' trial conducted by Janssen in South Africa, and the availability of a limited amount of vaccine doses, provide the rationale for a cohort study of vaccinated HCWs to inform the larger vaccine rollout.

Study participants Health Care workers age 18 and above working in the South African public and private health care sector (N=500 000) Study sites Department of Health Vaccine administration sites across South Africa supported by the Sisonke (Together) (VAC31518COV3012) trial Research Site Investigators and Study Staff

Study duration Participants will receive a single dose of vaccine at enrolment; to monitor outcomes the DATCOV surveillance system and NICD line list will be reviewed for up to 2 years post-vaccination.

A sub-cohort (approx. 850-1000 people) consisting of special sub-populations will be followed up at approx. 1, 3, 6 weeks and 6 months post vaccination. This group will also have outcomes monitored for up to a further 18 months, bringing their total follow-up duration to 2 years post-vaccination

Study products Ad26.COV2.S by Janssen administered as a single injection

Primary objectives • To assess the effectiveness of Ad26.COV2.S vaccine on severe COVID, hospitalizations and deaths in HCWs as compared with the general unvaccinated population in South Africa.

Secondary objectives • To estimate the incidence of symptomatic SARS CoV-2 infections in HCW

* To estimate vaccine uptake among HCWs in South Africa
* To monitor the genetic diversity of breakthrough SARS CoV-2 infections To monitor immunological responses (neutralising, non-neutralising antibodies and T cell responses) in HCWs with breakthrough infections
* To measure baseline SARS CoV-2 antibody testing to evaluate pre-existing immunity in up to 100 000 HCWs.
* In a subgroup of participants (approx. 850-1000 people) including representative sub-populations of interest, e.g. elderly, immune compromised:

* To compare serum neutralization and immune responses before and after vaccination at 0, 6 weeks and up to 6 months.
* To explore clotting parameters post vaccination at weeks 0, 1, 3.
* To monitor for asymptomatic infection

Exploratory objectives To set up a comprehensive safety desk and establish a link between the national pharmacovigilance system to assist with monitoring safety and any unexpected adverse effects

• To monitor the effectiveness of the single dose Ad26.COV2.S COVID-19 vaccine (Biological): To monitor the effectiveness of the single dose Ad26.COV2.S COVID-19 vaccine among health care workers (HCW) as compared to the general unvaccinated population in South Africa

Primary outcomes

• Number of severe COVID, hospitalizations and deaths in HCWs as compared with the general unvaccinated population in South Africa [24 Months]: Rates of hospitalizations and deaths among vaccinated HCWs versus general unvaccinated population

Secondary outcomes

• The number of symptomatic SARSCoV-2 infections among vaccinated HCWs [24 Months]: Incidence rate of SARS CoV-2 infection as indicated by self-report and validation in national laboratory records. Rates of severe disease in HCW who are found to be RT-PCR positive at anytime up to 2 years post vaccination
• The measure of genetic diversity of breakthrough SARSCoV-2 infections [24 months]: Genetic diversity of breakthrough infection virus as determined by whole genome sequencing. This will be recovered from national laboratories.
• Monitoring for asymptomatic infection in a sub-set (10 000) of HCWs [24 Months]: Rates of asymptomatic infection at baseline and follow up using SARS CoV-2 virus and antibody testing.
• Monitor for safety and any unexpected adverse effects of the vaccine administration -pharmacovigilance [24 Months]: Conduct Pharmacovigilance to monitor for safety and adverse events Numbers of safety events and/or unexpected adverse effects reported to the study team Monitor pregnancies and pregnancy outcomes reported to safety desk.
• The vaccine uptake among HCWs in South Africa [12 Months]: Proportion of HCWs approached for study participation taking part in the study and receiving the vaccine

Other outcomes

• To monitor for safety and any unexpected adverse effects of the vaccine administration [24 Months]: To conduct pharmacovigilance to monitor for safety and any unexpected adverse effects of the vaccine administration

Sex: All, ages: 18 Years to 105 Years, accepts healthy volunteers

Inclusion criteria

* Age 18 and older
* Health care worker in the private or public service
* The President and Deputy President of South Africa* (The President and Deputy President of South Africa have been included in the protocol to address the issue of vaccine hesitancy. )
* Willingness and ability to comply vaccination plan and other study procedures.
* Capable of giving electronic or personal signed informed consent as described in Appendix 5, which includes compliance with the requirements in this protocol.

Inclusion criteria for the sub-cohort

* Age 18 and older
* Health care worker in the private or public service
* Willingness and ability to comply with all scheduled visits, vaccination plan, laboratory tests, and other study procedures, with follow-up at an ENSEMBLE site.
* Capable of giving electronic or personal signed informed consent as described in Appendix 5, which includes compliance with the requirements in this protocol.

Exclusion criteria

* Any significant acute or chronic medical condition, situation or circumstance that in the opinion of the PI/designee makes the participant unsuitable for participation in the study, or jeopardises the safety or rights of the participant
* Participant reports being pregnant at time of enrolment, planning conception within 3 months.
* Participants who report breastfeeding at the time of enrolment will be excluded.
* Current participation in any other research studies that would interfere with the objectives of this study. The determination of whether participation in another study would be exclusionary for a given participant will be made by the PI/designee.
* History of severe adverse reaction associated with a vaccine and/or severe allergic reaction (e.g., anaphylaxis) to any component of the vaccine.
* Participants who have experienced major venous and arterial thrombosis occurring with thrombocytopenia following vaccination with any COVID-19 vaccine should not enrol in Sisonke.
* Participants with a history of heparin-induced thrombocytopenia.

Note:

• Vaccination within 14-90 days with other COVID19 or non-specific vaccines are not exclusionary but should be discussed with study PI or designee.

Conditions of interest:

We note that international reports of VITT have not identified a risk factor, nor does there appear to be any prothrombotic state that indicates a risk factor for this immune response.

Nevertheless, the Sisonke study will enrol participants with chronic history of severe clotting disorders only after consultation and approval of the study Protocol Safety Review Team (PSRT).

We have identified certain specific conditions of special interest such as:

* cerebral venous sinus thrombosis,
* antiphospholipid syndrome
* Individuals on therapeutic anticoagulants for current or previous arterial or venous thrombosis or embolism

• Results publication: Jacobson BF, Schapkaitz E, Takalani A, Rowji PF, Louw V, Opie J, Bekker LG, Garrett N, Goga A, Reddy T, Zuma NY, Sanne I, Seocharan I, Peter J, Robinson M, Collie S, Khan A, Takuva S, Gray G. Vascular thrombosis after single dose Ad26.COV2.S vaccine in healthcare workers in South Africa: open label, single arm, phase 3B study (Sisonke study). BMJ Med. 2023 Mar 23;2(1):e000302. doi: 10.1136/bmjmed-2022-000302. eCollection 2023. PMID 37063238
• Results publication: Takuva S, Takalani A, Seocharan I, Yende-Zuma N, Reddy T, Engelbrecht I, Faesen M, Khuto K, Whyte C, Bailey V, Trivella V, Peter J, Opie J, Louw V, Rowji P, Jacobson B, Groenewald P, Dorrington RE, Laubscher R, Bradshaw D, Moultrie H, Fairall L, Sanne I, Gail-Bekker L, Gray G, Goga A, Garrett N; Sisonke study team. Safety evaluation of the single-dose Ad26.COV2.S vaccine among healthcare workers in the Sisonke study in South Africa: A phase 3b implementation trial. PLoS Med. 2022 Jun 21;19(6):e1004024. doi: 10.1371/journal.pmed.1004024. eCollection 2022 Jun. PMID 35727802
• Results publication: Bekker LG, Garrett N, Goga A, Fairall L, Reddy T, Yende-Zuma N, Kassanjee R, Collie S, Sanne I, Boulle A, Seocharan I, Engelbrecht I, Davies MA, Champion J, Chen T, Bennett S, Mametja S, Semenya M, Moultrie H, de Oliveira T, Lessells RJ, Cohen C, Jassat W, Groome M, Von Gottberg A, Le Roux E, Khuto K, Barouch D, Mahomed H, Wolmarans M, Rousseau P, Bradshaw D, Mulder M, Opie J, Louw V, Jacobson B, Rowji P, Peter JG, Takalani A, Odhiambo J, Mayat F, Takuva S, Corey L, Gray GE; Sisonke Protocol Team; Sisonke Study Team. Effectiveness of the Ad26.COV2.S vaccine in health-care workers in South Africa (the Sisonke study): results from a single-arm, open-label, phase 3B, implementation study. Lancet. 2022 Mar 19;399(10330):1141-1153. doi: 10.1016/S0140-6736(22)00007-1. PMID 35305740

• Glenda E Gray, MBChB, Principal investigator, Non-Executive Director