Introduction Active vaccine safety surveillance (VSS) can complement passive VSS while overcoming the inherent limitations of spontaneous reporting systems. However, active VSS is rarely implemented in sub-Saharan Africa. We undertook active VSS of COVID-19 vaccines in Kenya. Methods We conducted a post-authorization cohort event monitoring study in Kilifi County, Kenya. Eligible individuals who had received any dose of any COVID-19 vaccine brand were followed up weekly over 13 weeks for adverse events, including hospitalization. A subset of participants was followed up daily for one week for solicited systemic reactogenicity events (chills, fatigue, fever, headache, joint pain, malaise, muscle aches, nausea). Follow up was done through telephone calls and/or short message service (SMS) with data captured electronically. Reports of adverse events following immunization (AEFI) were submitted as per national guidelines. We aimed to enroll 10,000 participants into the cohort and 1,000 participants into the reactogenicity sub-study. The daily prevalence of reactogenicity events was compared to the 3-day pre-vaccine average prevalence using McNemar's test. The association of baseline characteristics with any systemic reactogenicity event was assessed using logistic regression. Results Between 28th September 2022 and 30th June 2023, a total of 2,440 participants were enrolled into the cohort, out of which 1,000 systematically sampled participants were included in the reactogenicity sub-study. Most of the participants were aged 17-39 years (1683; 69.0%) and were female (1895; 77.7%); 535 (28.2%) female participants were pregnant. Only 34.4% of 814 participants contacted by SMS responded appropriately. In the reactogenicity sub-study, 595 (62.2% of 956 completing follow-up) participants reported ≥1 systemic reactogenicity events. The three most frequently reported were fatigue (422; 44.1%), headache (370; 38.7%), and malaise (346; 36.2%). The proportion of severe systemic reactogenicity events ranged from 2.3% (22) for nausea to 5.0% (48) for malaise. Except for headache, the prevalence of systemic reactogenicity events was significantly higher in the first two days post-vaccination than in the three days prior to vaccination (p-values <0.05). The odds of reporting solicited systemic events were higher among non-pregnant women (adjusted odds ratio [aOR] 1.81; 95% CI 1.28-2.55) and pregnant women (aOR 1.69; 1.03-2.78) than among men. They were also higher among individuals receiving Johnson & Johnson (aOR 2.05; 1.40-3.00) or Moderna (aOR 4.19; 2.34-7.51) vaccine than among Pfizer vaccine recipients. The prevalence of pregnancy complications was 2.6% (95% CI 1.4-3.5%) against a background prevalence of 3-49%. Conclusion Systemic reactogenicity events following COVID-19 vaccination were non-severe and transient. There was no evidence of an elevated risk of pregnancy-related complications. The utility and feasibility of future active VSS studies could be improved by addressing context-specific challenges to enrollment and SMS-based follow-up.

A.A. reports institutional grants from the Gates Foundation, National Institute for Health and Care Research (NIHR), Wellcome Trust, Medical Research Council and FCDO, meeting/ travel support from the Gates Foundation, and an advisory role in a World Health Organization committee. E.W.K reports institutional grants from the Gates Foundation and FCDO, and meeting/ travel support from the Gates Foundation. The other authors have no interests to declare.

The study was funded by the Foreign Commonwealth & Development Office (FCDO; Project Number 300708-159). The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report, or in the decision to submit the paper for publication.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

1. Ethics committee of Kenya Medical Research Institute Scientific and Ethics Review Unit(#4486) gave ethical approval for this work. 2. Ethics committee of Oxford Tropical Research Ethics Committee(#28-22) gave ethical approval for this work. 3. Ethics committee of London School of Hygiene & Tropical Medicine Research Ethics Committee(#28013) gave ethical approval for this work

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

The deidentified data set and other supplementary materials have been published on the Harvard dataverse server. This work is licensed under a Creative Commons Attribution 4.0 International (CC BY 4.0) license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.