The CEM program was prospective, active surveillance designed to monitor the reactogenicity and AEFI with AstraZeneca and Moderna COVID-19 vaccines in Nigeria in alignment with the WHO protocol template for CEM for safety signal detection after vaccination with COVID-19 vaccines [11]. The CEM took place in one state in each of the 6 geo-political zones in Nigeria. The states—Bauchi, Edo, Enugu, Federal Capital Territory, Kaduna, and Lagos— were selected based upon security, stability, and the existence of infrastructure to conduct vaccine safety surveillance. In each state, one tertiary health facility and five primary health facilities were purposively selected for inclusion in the surveillance program. These sites all contained COVID-19 vaccination clinics offering both AstraZeneca and Moderna COVID-19 vaccines and were high-volume health facilities with adequate staffing, administration spaces, functional information technology infrastructure, and with an average of 25 persons vaccinated daily with a COVID-19 vaccine.

Consenting individuals aged ≥18 years who received the first dose of any COVID-19 vaccine from the selected health facilities were enrolled. Individuals who were already vaccinated against COVID-19 before the day of enrollment and those unable to comply with surveillance program procedures were excluded. To facilitate timely data collection during the pandemic, participation was limited to persons with access to mobile phones (applies to >90 % of Nigerian adults), defined as ownership of or access to a family member’s mobile phone.

A total sample size of 10,000 participants was estimated to rule out events with a frequency of 1 per 3333 at an alpha level of 0.05 if no event was detected [16]; this allows for the detection of uncommon events (≥1/1000 and < 1/100) and potentially the detection of rare events (≥1/10,000 and < 1/1000), as defined by the Council for International Organizations of Medical Sciences [17,18]. With a 10 % buffer for loss to follow-up, the target for enrollment was 12,000 (approximately 2000 participants per state).

Enrollment occurred at the selected health facilities from 1 September to 30 October 2021. The enrollment target was equally allocated across the 36 selected facilities: 334 participants per facility. Participants were enrolled sequentially at each facility until the day the facility enrollment quota was met. Some facilities exceeded their quota due to the high volume of vaccine recipients on the last enrollment day. Eligible, consenting participants were enrolled at the time of vaccination using a tablet-based questionnaire adapted from the WHO adverse drug reaction reporting tool [19], using CSPro (Census and Survey Processing System) software. Questionnaires were administered face-to-face by data entry clerks at the enrollment facilities and information was entered directly into tablets. The questionnaire collected information on demographic characteristics, vaccine exposure, participant-reported pre-existing medical conditions (defined below), solicited systemic symptoms experienced within three days prior to vaccination, and contact information of the participant and next-of-kin for follow-up data collection.

Data collectors conducted follow-up interviews over a three-month period via phone calls. Consenting participants were called on days 0 (within 24 h of vaccination), 3, 7, and every 7 days thereafter for three months, asking about events experienced since the last follow-up call. The same follow-up schedule was restarted if a participant received a second dose of any of the approved COVID-19 vaccines, per the country vaccination guidance. Information collected at enrollment was hosted on a custom CEM Activity Management Information System database. The follow-up information, obtained during phone call interviews, was captured via a web form interface of the CEM Activity Management Information System on a tablet or laptop. Response data were linked to the enrollment data using the participant’s unique identifier. Information on reactogenicity was collected on days 0, 3, and 7 after the first and second-dose vaccination; participant-reported medically attended events, hospitalization, and COVID-19 testing were solicited at every follow-up call. At the time of surveillance, mixed vaccine series were not permitted in Nigeria; therefore, there were no heterologous first and second-dose vaccine schedules. When surveillance personnel were unable to reach the participant directly after 5 attempts, they called the listed next-of-kin for follow-up. The follow-up of participants was concluded in March 2022.

The main outcome variables were local and systemic reactogenicity, medically attended events (MAEs), and serious adverse events (SAEs). Local reactogenicity was defined as inflammatory changes around the injection site, including pain, swelling, hardening (induration), warmth, redness (erythema), bruise, or itching occurring within 0–7 days of the first or second vaccine dose. Systemic reactogenicity was defined as fever, chills, headache, malaise, tiredness, joint pain, muscle ache, dizziness, cough, or nausea occurring 0–7 days post-vaccination. In addition to these specific symptoms solicited, any other participant-reported symptoms were captured during the 0–7-day period and at subsequent follow-up calls. Pre-vaccination systemic symptoms were defined as fever, nausea, malaise, chills, headache, joint pain, muscle ache, or fatigue within 3 days prior to the first dose COVID-19 vaccination. History of medical conditions was defined as one or more of the following participant-reported conditions: chronic respiratory, heart, or liver conditions, renal diseases, diabetes, immunocompromised/immunosuppressed conditions, obesity, and allergies [11].

Reported events that led participants to seek medical care from a health practitioner or pharmacist during any period of follow-up were classified as MAEs. SAEs, according to the WHO definition, included “events that result in death, are life-threatening, require in-patient hospitalization or prolongation of existing hospitalization, result in persistent or significant disability/incapacity, or are congenital anomalies or birth defects” [20]. Events that resulted in inpatient hospitalizations or death were identified and reported by the participant or next-of-kin. All SAEs were documented but participants with more than one SAE were only counted once (e.g., if a person was hospitalized and subsequently died).

All deaths reported during the CEM surveillance program were investigated by the Disease Surveillance and Notification Officers (DSNOs) at the local government area where the event occurred. Per routine surveillance, the local DSNOs sent an investigation report and laboratory findings to the State DSNO, who sent the dossier to the National Primary Health Care Development Agency (NPHCDA), where it was then collated and presented at the National Expert Committee (NEC), an independent group to assess potential causal association of conditions with the two COVID-19 vaccines. The NEC conducted causality assessments using the WHO standards, including the WHO AEFI reporting form and the AEFI causality assessment user manual for classification (2019 update) [1,21].

Hospitalizations that did not result in death were not assessed by the NEC. The surveillance team conducted an internal classification exercise to document reported reasons for hospitalization, but no causality assessments were made.

Participant characteristics and vaccine information at enrollment were summarized using descriptive statistics. All data were included until the time of participant completion in the surveillance program or until lost to follow-up; participants with at least one follow-up were included in the MAE and SAE analyses. Missing values were not replaced. All reported events and diagnoses were coded using MedDRA Preferred Terms for analysis. Frequencies of participants reporting reactogenicity, MAEs, and SAEs were stratified by vaccine brand and reported as percentages grouped by age, sex, history of medical condition, pre-vaccination systemic symptoms, and previous COVID-19 diagnosis. Proportions of participants with reported events were calculated from the post-vaccination observational period. Data were analysed using STATA version 16.

The protocol was approved by the National Health Research Ethics Committee, Nigeria (approval number NHREC/01/01/2007) and the University of Maryland, Baltimore institutional review board. The U.S. Centers for Disease Control and Prevention (CDC) determined the protocol to be non-research.

Participation was voluntary. Written informed consent was obtained from all participants, who were able to withdraw from the CEM program at any time.

Overall, 12,317 participants were enrolled across the 6 states (Fig. 1), with a range of 2024–2078 participants per state. Among those enrolled, 6990 (56.7 %) received AstraZeneca vaccine, and had a median age of 39 years (interquartile range (IQR) 29–51 years), and over half (4062, 58.1 %) were male. Among the 43.3 % (5327) of participants who received Moderna vaccine, the median age was 37 years (IQR 29–49 years), and 2973 (55.8 %) were male (Table 1).

Of the 12,317 enrolled participants, 11,911 (96.7 %) (AstraZeneca 6662 (95.3 %), Moderna 5249 (98.5 %)) participants’ phone numbers were reachable (Fig. 1). Loss to follow-up over time point ranged from 0.4 to 5.6 %, with 10,618 (85.8 %) participants completing all surveillance timepoints.

Among those reached, 11,046/11,911 (92.7 %) (AstraZeneca 6167 (56 %), Moderna 4879 (44 %)) completed at least one follow-up interview on day 0, 3, or 7 following the first dose vaccination and were included in the reactogenicity analyses. Of 6167 AstraZeneca vaccine recipients included in the reactogenicity analyses, 2685 (43.5 %) reported local reactions and 2456/6167 (39.8 %) reported systemic reactions within 7 days of receiving the first vaccine dose. Among those reporting local reactions within 7 days following vaccination, 47.7 % (1281/2685) were female, 23.5 % (629/2.685) reported history of a medical condition, and 37.0 % (994/2685) reported experiencing systemic symptoms within 3 days pre-vaccination. Among people reporting systemic reactions within 7 days of vaccine receipt, 45.6 % (1119/2456) were female, 23 % (564/2456) reported history of a medical condition, and 37.7 % (926/2456) reported systemic symptoms within 3 days pre-vaccination (Table 2A). Among AstraZeneca vaccine recipients who experienced local reactions within the first 7 days, the majority reported pain at injection site after both vaccine doses, while bruising around the injection site was the least reported reaction. Fever was the most reported systemic reaction after receiving both doses of AstraZeneca vaccine, while cold and cough and shortness of breath were least reported (Fig. 2B).

Of the 6167 AstraZeneca recipients, 3891 (63.1 %) received a second vaccine dose. Among them, local and systemic reactions were reported by 23.1 % (897) and 18.7 % (727), respectively. Among people reporting local reactions following the second dose of AstraZeneca vaccine, 48.6 % (436/897) were female, 26.5 % (237/897) reported history of a medical condition, and 39.6 % (355/897) experienced pre-vaccination systemic reactions before the second dose. Among those reporting systemic reactions, 46.9 % (341/727) were female, 25.6 % (186/727) reported history a of medical condition, and 38.2 % (278/727) reported pre-vaccination systemic reactions (Table 2A).

Among the 4879 participants who received a first dose of Moderna vaccine, local and systemic reactions within 7 days of vaccination were reported by 72.4 % (3533/4879) and 42.8 % (2087/4879), respectively. Among people reporting local reactions within 7 days of a first dose of Moderna vaccine, 46.7 % (1612/3533) were female, 24.9 % (880/3533) reported history of a medical condition, and 25.7 % (1389/3533) experienced pre-vaccination systemic symptoms. Among those reporting systemic reactions, 46.7 % (975/2087) were female, 24.9 % (535/2087) reported history of a medical condition, and 39.3 % (891/2087) reported systemic symptoms 3 days pre-vaccination (Table 2B).

Overall, 3978/4879 (81.5 %) Moderna vaccine recipients received a second dose vaccine; 49.7 % (1979) and 42.2 % (1680) reported local and systemic reactions within the first 7 days, respectively. Among those reporting local reactions, 47.5 % (941/11979) were female, 26.5 % (523/1979) reported history of a medical condition, and 39.3 % (778/1979) reportedly experienced pre-vaccination systemic reaction. Among those reporting systemic reactions post second Moderna dose, 45.7 % (768/1680) were female, 26.7 % (449/1680) reported history of a medical condition, and 40.1 % (673/1680) experienced pre-vaccination systemic reaction (Table 2B). Injection site pain was the most commonly reported local reaction after receiving the first and second doses of Moderna vaccine (Fig. 2A). Fever was the most reported systemic reaction (Fig. 2B).

Overall, 5.3 % (355/6662) of AstraZeneca and 8.2 % (431/5249) of Moderna vaccine recipients reported a MAE during the surveillance period (Table 3). The most common reasons for seeking any type of care were fever (AstraZeneca 10.1 %, Moderna 11.8 %), body pain (AstraZeneca 7.6 %, Moderna 7.7 %), and respiratory symptoms (AstraZeneca 6.5 %, Moderna 6.5 %) (Fig. 3).

Overall, 84/11,911 (0.7 %) participants reported a SAE; (0.7 % (48/6662) AstraZeneca recipients and 0.7 % (36/5249) Moderna recipients) (Table 4); 75/11,911 (0.6 %) of those participants were hospitalized during the surveillance, with fever and tiredness among the most reported events that led to hospitalization (Fig. 4). Two hospitalized patients died. Nine other participants died, per their next-of-kin. Causality assessment was conducted for all 11 reported deaths. Autopsy was not conducted and there was insufficient evidence to classify these cases without a valid diagnosis (cause of death). However, per the NEC, there was no evidence to suggest that the deaths were vaccine-related (Supplementary Table 1).

According to internal classification by the surveillance team (not causality assessment) among the 73 hospitalized patients who experienced 151 symptoms at admission, 37/73 (50.7 %) patients were hospitalized for a known infectious etiology or pre-existing medical condition (Supplementary Table 2).

There were limitations to this surveillance program. Because events were solicited from vaccine recipients, there was the potential for overreporting. All events were participant-reported and were not validated by clinical personnel or by medical chart review. However, all deaths detected were reported to the Nigerian regulatory authority for investigation and causality assessment. No autopsies were performed, limiting available information for assessment. There was potential variability of the qualifications and professional experience of the personnel administering the vaccines, which could influence the incidence of certain adverse events. Further, there was the potential for recall bias on concurrent medications or other medical interventions that could confound the relationship between the vaccination and reported AEFI. Reported SAEs that did not result in death were not investigated by the NEC, thus some events resulting in hospitalization may or may not have been vaccine-related (e.g., high fevers). Participation in this surveillance program was only offered to individuals with access to mobile phones; however, current data on mobile phone subscriptions indicate that over 90 % of Nigerian households have access to a mobile phone [37]. While we do not expect differences in AEFI between vaccine recipients with and without access to mobile phones, the healthcare-seeking behaviours, hence the incidence of reported MAEs and SAEs may vary, as there is evidence of an association between mobile phone ownership and healthcare-seeking behaviour and access to health services [38–40]. Because two vaccines were in use at the time of implementation, our sample size was not reflected per vaccine product. Similarly, our sample size was insufficient to detect rare but potentially life-threatening conditions, such as thrombosis with thrombocytopenia syndrome, a rare AEFI recognized to be causally associated with adenoviral vector COVID-19 vaccines [41]. Data on symptom onset from the time of vaccination were not available. Future studies should include information on symptom onset to allow for identification of clustering of AEFI. We did not collect the number of all vaccine recipients screened and therefore do not know the proportion of vaccinated individuals that refused or were ineligible to participate. Last, we did not assess AEFI in persons younger than 18 years old. Since completing this surveillance program, COVID-19 vaccines have been permitted for use in younger age groups (<18 years old) and other special populations, such as pregnant women. To address this gap in locally generated data, immunization and regulatory authorities in Nigeria are implementing an expanded CEM among a larger cohort and with a longer duration of follow-up.