Rapid global approval of coronavirus disease 2019 (COVID-19) vaccines and concurrent introduction in high-income countries and low- and middle-income countries (LMIC) highlights the importance of equitable safety surveillance of adverse events following immunization (AEFIs). We profiled AEFIs to COVID-19 vaccines, explored reporting differences between Africa and the rest of the world (RoW), and analyzed policy considerations that inform strengthening of safety surveillance in LMICs.
Using a convergent mixed-methods design we compared the rate and profile of COVID-19 vaccines’ AEFIs reported to VigiBase by Africa versus the RoW, and interviewed policymakers to elicit considerations that inform the funding of safety surveillance in LMICs.
With 87,351 out of 14,671,586 AEFIs, Africa had the second-lowest crude number and a reporting rate of 180 adverse events (AEs) per million administered doses. Serious AEs (SAEs) were 27.0%. Death accounted for about 10.0% of SAEs. Significant differences were found in reporting by gender, age group, and SAEs between Africa and the RoW. AstraZeneca and Pfizer BioNTech vaccines were associated with a high absolute number of AEFIs for Africa and RoW; Sputnik V contributed a considerably high rate of AEs per 1 million administered doses. Funding decisions for safety surveillance in LMICs were not based on explicit policies but on country priorities, perceived utility of data, and practical implementation issues.
African countries reported fewer AEFIs relative to the RoW. To enhance Africa’s contribution to the global knowledge on COVID-19 vaccine safety, governments must explicitly consider safety monitoring as a priority, and funding organizations need to systematically and continuously support these programs.
The African region reported fewer adverse events following immunization than the rest of the world.
There is no explicit policy by some donor organizations to fund safety monitoring in low- and middle-income countries.
Systematic and sustainable funding is needed for equitable safety monitoring.
There is low reporting of the adverse events (AEs) of pharmaceutical interventions (medicines and vaccines) in many countries across the world, particularly in low- and middle-income countries (LMICs) [1,2,3]. Monitoring the safety of pharmaceutical interventions will provide evidence to support the introduction of newer interventions and continued safe use of existing ones in LMICs and the rest of the world (RoW).
As of August 31, 2022, when the last update was made, 33 coronavirus disease 2019 (COVID-19) vaccines had been authorized for limited use or approved for full use around the globe . By December 15, 2022, about 13.03 billion doses of COVID-19 vaccines had been administered globally . Among the people in LMICs, 25.1% have received at least one dose of the vaccine within this period . As of December 13, 2022, 34.1% of Africa’s population has received at least one dose of a vaccine, with 27.8% being fully vaccinated .
The fast-tracked development of the COVID-19 vaccines and use of new technologies in their development have raised safety concerns [8, 9]. There have been reported cases of potentially serious but rare AEs such as thrombosis with thrombocytopenia syndrome (TTS), pericarditis, myocarditis, and Guillain-Barré syndrome (GBS) [10, 11]. Anaphylaxis and local and systemic reactions are other well-documented AEs with COVID-19 vaccines . These reports were identified from high-income countries’ (HICs’) with robust safety surveillance infrastructures.
Historically, there was a delay of many years between introducing new vaccines in HICs and LMICs. This delay allowed for the proper characterization of the safety profile of such vaccines before introduction in LMICs . More recently, the need to improve timely and equitable access to pharmaceutical products and vaccines in LMICs has led to the simultaneous introduction of such products in LMICs and HICs . The infrastructure for post-introduction pharmacovigilance (PIPV) in many LMICs remains relatively weak , thus creating the need for donor/funding organizations to support the establishment of safety surveillance systems in LMICs to ensure equitable safety surveillance . Not all LMICs can be funded for this, and priorities may need to be set. Thus, it is helpful to understand the policies and key considerations that inform which countries receive financial support to establish or strengthen existing systems. This work aims to profile the adverse events following immunization (AEFIs) with COVID-19 vaccines submitted to VigiBase—the World Health Organization’s (WHO’s) global database of individual case safety reports (ICSRs)—to explore the difference in reporting between Africa, with limited PIPV systems, and the RoW, and to understand the key considerations that inform the decisions made by donor organizations to strengthen safety surveillance systems in LMICs.
We undertook a convergent mixed-methods research , comprising quantitative analysis of AEFIs with COVID-19 vaccines reported to VigiBase and qualitative in-depth individual interviews of key policymakers from donor/funding organizations, to understand the policy considerations that inform the decision to support the establishment of safety surveillance systems in LMICs.
2.1 Quantitative Study Design, Setting, and Data Cleaning
We conducted secondary analysis of de-identified data on the AEs of COVID-19 vaccines reported to VigiBase from December 2020 to March 14, 2022. VigiBase is the WHO’s global database of ICSRs and contains over 30 million ICSRs of suspected AEs of medicines and vaccines submitted by over 170 member countries of the WHO Program for International Drug Monitoring (PIDM) since 1968. The database is continuously updated with new reports from passive surveillance systems, active surveillance studies, or other safety surveillance systems implemented by participating countries [17, 18].
The data obtained from VigiBase were descriptively analyzed at the individual AE level and not at the level of ICSRs. The dataset contains information on the vaccines associated with the reported AEFI, age group, and the gender of those reporting the AEFIs. It also contains information on whether the event was serious or not, the reason for seriousness, and the event's outcome, among other variables. An AEFI is defined as “any untoward medical occurrence that follows immunization and does not necessarily have a causal relationship with the usage of the vaccine. The adverse event may be any unfavorable or unintended sign, abnormal laboratory finding, symptom or disease” . The terms “adverse events” (AEs) and “adverse events following immunization” (AEFIs) are used interchangeably in this study. A serious adverse event (SAE) is “an adverse reaction that results in death, is life-threatening, requires in-patient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a congenital anomaly/birth defect” .
Data on administered doses of COVID-19 vaccines were obtained from the published literature to estimate reporting rates for each WHO region. Where no data on administered doses were readily available in the public domain as far as we were aware, the administered doses were extrapolated using available population data for the region and available data on doses administered per 100 persons (see electronic supplementary material [ESM]# 1 for data sources). Similarly, data from the WHO AFRO region on administered doses of COVID-19 vaccines received by vaccine type were used in combination with the total number of administered doses to estimate the administered doses for each vaccine and to facilitate the calculation of reporting rate by vaccine type for the region. Similar calculations were not done for other regions due to the non-availability of such data for some regions. Data were analyzed using STATA/BE 17.0 to provide descriptive statistics on demographic characteristics. Prior to data analysis, observations that were coded as either “unknown,” “other,” or “not applicable” were omitted from variables such as gender, age group, outcome, seriousness, and reporting type to ensure consistency across analyzed data. Observations where the vaccine name could not be definitively established were also omitted. Care was taken to ensure that the observations were omitted from only the relevant variables and not dropped from the entire dataset; hence, some totals may not always add up. The frequency of AEFIs was calculated by vaccine type, age group, and gender. Reporting AE rate per 1 million administered doses by vaccine type was not calculated for the RoW due to the non-availability of data on vaccine distribution/administration for some regions. The frequency of AEFIs by Medical Dictionary for Regulatory Activities (MedDRA®) system organ class (SOC) and the preferred term were assessed and reported as percentages. MedDRA® is a standardized medical terminology used for coding AEs in clinical trials and pharmacovigilance. Chi-square test was used to detect any differences in the proportion of reported AEFIs between Africa and the RoW for key parameters.
2.2 Qualitative Study Design
2.2.1 Study Population/Sampling Approach
Key policymakers from some donor/funding or global organizations that support safety surveillance of COVID-19 vaccines in LMICs at the time of the study were invited to participate in the virtual interview. We used purposeful sampling to identify interview participants to ensure the inclusion of persons who are key policy/decision-makers or those leading implementation of safety surveillance activities within the organizations. This sampling strategy allowed us to select participants based on information richness, as we sampled for individuals who would be information-rich cases, capable of providing us with rich data to help answer the research question. The first author compiled a list of 18 potential participants and their email addresses, with support from a key informant from one of the funding/implementing organizations. A request for an in-depth interview and an informed consent form were sent via email to all persons on the list.
2.2.2 Data Collection
Single, in-depth individual interviews were conducted with 12 key policymakers. Interviews were conducted with the aid of a semi-structured interview guide (see ESM# 2) that covered the following topics: (1) involvement in the safety surveillance of vaccines; (2) institutional policies that inform funding for safety surveillance; (3) criteria for selecting LMICs to be funded; and (4) key challenges and benefits associated with safety surveillance in LMICs. The interview guide allowed the interviewer to ask probing questions to gain greater insights into the interviewee’s thoughts and experiences. The first author conducted in-depth interviews in English, and they lasted approximately 45–90 mins. Interviews were conducted virtually via Zoom at a time chosen by the participant and were video and audio recorded with written informed consent from participants.
2.2.3 Data Analysis
Data analysis was done using an inductive, thematic, content analysis approach to develop categories . Following a complete review of the dataset, a subset of transcripts was open-coded to identify a draft codebook that represented interviewees’ experiences with funding and or implementing safety surveillance for vaccines. The codebook was piloted and reviewed with members of the study team and finalized. All transcripts were coded using Dedoose® qualitative data management software .
The coded data were reviewed inductively to identify thematic content, which resulted in a set of draft categories. Final category and subtheme development involved an iterative process of reviewing the draft categories, coded data, and revisiting the interview scripts as necessary to provide additional depth and detail.
Finally, the quantitative and qualitative results were integrated using a joint display technique  to show where data from the quantitative review and qualitative interview converged or overlapped. See ESM# 3 for an illustration of the convergent mixed-methods approach used for the study.
3.1 Profile of AEs with COVID-19 Vaccines
A total of 2,353,018 ICSRs containing 14,671,586 AEs of COVID-19 vaccines were contained in VigiBase as of March 2022. There were multiple AEs reported within ICSRs, with an average of six AEs per ICSR. The African region contributed the second-lowest number of overall reported AEs both in absolute numbers 87,351 (0.6%) as well as overall estimated reporting rates (180 per estimated million doses administered); see Table 1. AEs from the spontaneous (or passive) reporting system accounted for 96.7% of the reported AEs from Africa, whereas 3.3% were from studies. For RoW, these percentages were 95.0% and 5.0%, respectively. Africa’s total contribution of AEs from studies was 2890 (0.4%) compared to 725,414 (99.6%) from the RoW (Table 2).
Overall, and for the RoW, reported AEs for females (73.6%) were higher than for males (26.4%). Within Africa, reporting between females and males was well balanced, with 53.2% reporting from females and 46.8% from males. Persons aged 18–44 years in both Africa and RoW had the highest number of AEs, at 63.4% and 46.7% of total reported AEs, respectively.
SAEs accounted for 12.2% of AEs reported from Africa compared to 27.1% for the RoW. Death was reported in 728 (10.1%) of SAEs from Africa as the reason for seriousness, compared to 211,546 (9.6%) for the RoW. Regarding outcome, 61.4% of the AEs reported from the African region had resolved at the time of reporting, similar to 58.2% of the AEs from the RoW.
3.2 Distribution of AEs by Vaccine Type and SOC
For the RoW, the Cormirnaty/Pfizer BioNTech vaccine, with 47.8%, had the highest percentage of reported AEs in absolute terms, followed by Vaxzevria/AstraZeneca, with 24.7%. For the African region, Vaxzevria/AstraZeneca had the highest, at 71.0%, followed by Cormirnaty/Pfizer BioNTech vaccine, at 12.3% (Table 3). For AE reporting rate per 1 million doses administered by identifiable vaccine type, AstraZeneca had the highest AE rate, at 701, closely followed by Sputnik V with 623 AEs per 1 million doses administered (Table 4). These rates are much higher than the overall rates of 180 per million doses for the overall reports (Table 1) and 178 per 1 million doses for identifiable vaccine types (Table 4) within the region. Similarly, the African region had a relatively large percentage of AEs reported for the Sputnik V vaccine (20.3% of all reported AEs for this vaccine).
For both Africa and the RoW, general disorders and administration site disorders were the most frequently associated SOC, at 34.7% and 26.5%, respectively. This was followed by nervous system disorders and musculoskeletal and connective tissue disorders (Africa 20.3%/RoW 13.7% and Africa 11.5%/RoW 11.2%, respectively). Headache (11.4%) was the most frequently reported AE for Africa, followed by pyrexia (8.6%) and injection site pain (7.5%), while chills (5.0%), headache (4.6%), and dizziness (4.3%) were the top three AEs for the RoW (Table 3).
3.3 Demographics of Interview Participants
A total of 12 key policymakers who accepted to be interviewed and consented were interviewed. Nine of the interviewees were male. Eight of them resided in the USA, two in Switzerland, and one each in Malaysia and South Africa.
3.4 Categories and Subthemes
Our qualitative findings revealed that many funding organizations do not have an explicit policy that informs the decision to fund LMICs for safety surveillance. Such decisions were often influenced by considerations about country priorities, the utility of the evidence generated, the perceived value added to global health by safety systems, and practical implementation issues. The main findings are summarized into three main categories and subthemes. A joint display table (Table 5) illustrates where findings from the quantitative study overlap with themes identified in the qualitative study; additional qualitative evidence is provided in the table to further support the themes described below.
3.4.1 Category 1: (Not) Prioritizing Safety Surveillance as a Key Component of Health System Strengthening
Prioritizing coverage over safety Participants expressed the view that many LMICs placed more emphasis on rates of overall vaccine coverage and did not perceive safety as a priority. Thus, the majority of funds available for health system strengthening (HSS) are dedicated to the procurement of syringes and needles, cold chain equipment, supply chain logistics, and staff training that directly support vaccine coverage. A minuscule amount of the funds available for HSS is used to support safety surveillance.
The vast majority of the health system strengthening funding is geared towards trying to address issues around making sure that children get vaccinated, or in GAVI jargon “coverage.” (Key Informant-05, male policymaker)
Playing the Ostrich Although safety monitoring is acknowledged as part of HSS, many countries are reluctant to prioritize safety because they fear that safety data will draw attention to vaccine safety issues. Participants opined that decision-makers sometimes prefer to avoid setting up safety monitoring systems and instead “play the ostrich,” believing that if they do not look for AEs, they will not find any, and consequently all will be well, and they will have peace.
The problem is that some health ministers want to stick their head in the sand and if there's a problem, they don't want to know about it. The problem is that with social media, the problem will surface anyway and they won't have any idea how to evaluate it. (Key Informant-07, male policymaker)
Adequate Handling of Data on AEs Participants noted that for countries to prioritize safety, there must be capacity within the country to handle safety issues. They advocated for strong collaborations between regulators and key stakeholders, and highlighted the importance of effective communication and feedback mechanisms. Participants emphasized the importance of relevant committees to undertake benefit–risk evaluation of safety signals, suggesting that in the absence of these committees, safety surveillance would remain a low priority in many LMICs.
Regulators also have to be responsive. In the sense that once they get the information, what do they do with the information? Once they have analyzed, if there is any finding …, do they also give feedback to the healthcare workers to say yes, we've seen this information, this is what we are getting? Because there has to be a two-way sort of feedback mechanism where those that are providing information also know that their time is not wasted. (Key Informant-12. female Policymaker)
3.4.2 Category 2: Perceived Utility of the Safety Surveillance System
Generate evidence for decision-making at the local level Participants explained that many LMICs lack systems to collect locally generated data. As a result, in-country, population-level decisions are based on data generated from HICs where the systems and infrastructure for generating such data are available.
One of the biggest challenges from the [organization name] perspective right now is the fact that we are making decisions for low- and middle-income countries based on data available in high income countries which I personally think is not correct. (Key Informant-11, male policymaker)
Interviews highlighted the potential of using data generated in LMICs to understand major disease patterns (morbidities and mortalities), as well as access to care in those settings. Such data are useful for benefit–risk analysis and can be leveraged to answer specific questions that may be relevant for the introduction or continued use of certain products in particular populations or geographic locations of interest. Localized safety surveillance systems can generate data to support course-correcting measures for public health programs and inform appropriate regulatory decisions. Participants shared experiences where local safety surveillance systems preemptively identified problems that could have derailed mass vaccination campaigns. Sometimes, these problems may not be related to an inherent characteristic of the vaccine product but to its handling and administration. One participant shared this example:
For example, in the episode in [Country X] where somebody used pancuronium [a muscle relaxant] as a diluent for a vaccine. What they discovered is that the vials looked very similar, same color, pattern and everything. (Key Informant-03, male policymaker)
Improving public/global health and equity Interviewees expressed the view that implementing safety monitoring should be an integral part of an effective global immunization strategy that seeks to achieve equity in global vaccine coverage and safety. They support safety surveillance systems as a vital component of the “complete package” that should accompany the introduction of any vaccine, with the expectation that safety surveillance is central to improving global health security and disease elimination/eradication.
I think it’s part of the package. I mean we would not be doing our job correctly if we were to offer countries vaccines and that was it and I mean we didn’t help them to set up the monitoring mechanisms and the distribution mechanisms and so on. And so vaccine safety and adverse effect reporting is a necessary part of that. (Key Informant-03, male policymaker)
A standard part of introducing a new intervention such as a vaccine is having a risk management plan that identifies potential risks and puts mitigation measures in place before any harm occurs. Participants indicated that, similar to the practice in HICs, having effective safety monitoring systems in LMICs will help to institutionalize risk management planning in parts of the world where it is not implemented as an early warning system.
It's a shame when you have a product that is accompanied for example with the risk management plan in a high-income country; but it can be used in the absence of risk management elsewhere, to me that is a disparity that I think we understand that there is a need to reduce those inequities and disparities in how products are managed in order to either reduce risk or mitigate risk. (Key Informant-09, male policymaker)
Building robust systems that contribute to global knowledge on vaccine safety Respondents noted that many safety surveillance systems in LMICs rely on spontaneous reporting systems, which in many cases are still rudimentary. These systems are limited because they mainly identify more common, expected, and well-documented AEs. Strengthening spontaneous reporting systems remains a key objective for funders:
For the spontaneous reporting, we sort of want all countries to have that. So, I think even when we're doing active surveillance strengthening, we want to make sure that some of that, some of that work is translating over to strengthening the passive system. (Key Informant-02, female policymaker)
Participants also noted that more robust surveillance systems that can identify rare, unexpected AEs are needed to improve LMICs’ contribution to actual vaccine–AEFI associations, which can increase local and global knowledge of vaccine safety.
If you have background rates of events and you can monitor that and do observed versus expected, so you know 10,000 people were vaccinated, you'd expect one event. If you saw 10, then you'd be concerned. But you can also use those cases to do more formal studies such as case control studies and case cohort studies and self-control studies. Basically, epidemiologic studies that allow you to see whether the association is real. (Key Informant-07, male policymaker).
3.4.3 Category 3: Practical Implementation Issues
Enabling and supportive political and bureaucratic environment within a country Participants indicated that politically stable countries with enabling governance and supportive bureaucratic systems make it easier for funding organizations to establish safety surveillance systems. Preexisting positive relationships fostered through ongoing projects were key considerations for funding organizations. Funders/implementers tended to avoid collaborations with countries that were perceived as having uncooperative bureaucracies, because they feared approval delays and political instability.
We've been wary of countries that are, you know, having a lot of political instability because of that buy-in issue and just the logistics of doing work in that setting. (Key Informant-02, female policymaker)
Product availability/product pipeline Participants noted that sometimes the decision to fund specific LMICs to establish active safety surveillance or to strengthen existing passive surveillance systems depends on where new vaccines or those in the pipeline will become available. According to an interviewee:
We put together a safety working group and one of the things they did was to look at the global health pipeline of when these new products are coming, like you know when are they coming, which of these products have let's say safety questions attached to them that you need more information on and then which countries are they going to… (Key Informant-01, male policymaker)
Existing capacity (technical and infrastructural) within a country The existing capacity to support safety surveillance within a country was identified by interviewees as a key consideration to support the establishment of a safety surveillance system. These capacities include basic infrastructure and a trained and experienced workforce.
It really comes down to: Do they have sufficient number of qualified individuals to carry it out, Do they have sufficient resources for it? Do they have the enabling legislation for it? Do they have the tools? (Key Informant-09, male policymaker)
Our quantitative study, which was mainly descriptive, found that countries in the African region reported relatively low numbers of AEs with COVID-19 vaccines compared to the RoW. About a quarter of all reported AEs in the dataset were serious, with hospitalization occurring in about 50% and death in 10% of the reports. Persons aged 18–44 years and females reported the greatest number of AEs for Africa and RoW, which can be expected given the relative size of this group. Well-documented local and systemic reactions including headache, pyrexia, injection site pain, dizziness, and chills were most frequently reported. General disorders and administrative site disorders, and nervous system disorders were the most affected SOCs. AstraZeneca and Pfizer BioNTech had the highest count of AEs in absolute terms for Africa and RoW, reflecting their widespread global use. In our qualitative studies, three main categories emerged from the insights shared by interview participants to explain how decisions to support LMICs to set up or strengthen existing surveillance systems are made. Many participants reflected that their organizations do not have an explicit policy for funding safety surveillance in LMICs. Such decisions tended to be based on how countries prioritize safety, the perceived utility/value of such safety surveillance systems, and the practical issues involved in setting up the systems.
The relatively low number of AEs with COVID-19 vaccines reported from the African region in our study is in line with other studies that have reported a lower reporting rate of AEs from Africa and other resource-limited settings [23, 24]. Historically, reporting of AEs in LMICs has always lagged behind reporting in HICs, where pharmacovigilance systems tend to be better established. A study showed that in 2015, the African and South-East Asian regions lagged behind most other regions in the number of reported AEFIs . Until recently, safety surveillance in LMICs was considered a luxury as countries focused more on improving access to pharmaceutical interventions, including vaccines. However, support from many donor organizations towards improving access has also brought support for establishing safety surveillance systems in line with the practice in HICs .
Our analysis showed that overall, a considerable number of the reported AEs in the dataset were serious (27%) regardless of reporting source (passive or studies). A smaller percentage was reported for Africa. Close to 10% of the SAEs for Africa and the RoW indicated death as the reason for seriousness. Siddhartha et al. reported a lower frequency of 1% fatality for the SAEs in their analysis of AEs from VigiBase® in 2021 . Within the first month of COVID-19 vaccination implementation, 9.2% (n = 640) of reports to the Vaccine Adverse Event Reporting System (VAERS) were SAEs, with 1.6% (n = 113) deaths . Africa’s contribution to the total SAEs in our data was less than 1%, with a statistically significant difference in reporting of SAEs and reporting by gender compared to the RoW. Given the morbidity and the economic and social burden imposed on individuals by SAEs [29, 30], monitoring systems that can pick up such reactions early and facilitate the implementation of preventive measures will be beneficial in Africa and other resource-constrained regions.
The AEs reported in this study are expected AEs that have been well documented from clinical trials and observational studies in HICs. In our study, systemic and local reactions, including headache, pyrexia, and injection site pain, were the top three most frequently reported AEs from the African region, while chills, headache, and dizziness were the top three in RoW. Gee et al. reported headache, fatigue, and dizziness as the most frequently reported symptoms in VAERs in the first month of vaccination with COVID-19 vaccines in the USA . Other studies have reported similar findings [12, 31]. These findings reflect the views of some interviewees that post-introduction safety surveillance systems in many countries, including LMICs, detect mainly well-known and well-documented events. Reporting of known AEs is valuable because it contributes to evaluating the actual incidence of known AEs in the post-marketing phase, but the value of more robust and rigorous systems for safety surveillance in LMICs cannot be overemphasized. Fewer AEs were reported from studies conducted in Africa (3.3%) compared to the RoW (5.0%). This may reflect the limited infrastructure and funding available for more robust and rigorous hospital or sentinel site-based safety surveillance, which is more likely to identify serious and unexpected SAEs faster. Expanding the safety surveillance infrastructure for Africa will be a necessary step towards enhancing the region’s active safety surveillance, promoting equitable safety monitoring, and contributing to global knowledge for protecting and promoting health.
Data from the African region showed that AstraZeneca, Pfizer BioNTech, and Janssen vaccines had higher absolute numbers of AEs. For the RoW, the order was Pfizer BioNTech, AstraZeneca, and Moderna. For the African region, AstraZeneca had the highest estimated rate of AEs per 1 million administered doses by vaccine type, followed by Sputnik V vaccine. Although Sputnik V constituted only about 1% of the vaccine doses administered within Africa as of April 28, 2022 , the high rate of reported AEs per 1 million doses relative to other vaccines administered in Africa is remarkable. This very high reporting rate for Sputnik V relative to other more widely distributed vaccines in Africa amplifies the concerns raised about the safety of vaccines from less established manufacturers  and the need for strong safety surveillance systems in Africa where such vaccines are likely to be distributed. Reporting rates by vaccine type for Africa could not be compared with the RoW due to limited data on vaccine distribution for some regions. The reported event rates are crude reporting rates, which should be interpreted with caution in the absence of information on background rates of the events in the African population.
Participants in the qualitative study alluded that many funding organizations do not have an explicit policy that supports the decision to fund safety surveillance in LMICs. Such decisions tend to be influenced by several considerations including how recipient countries prioritize safety surveillance, the perceived utility of safety surveillance systems to generate data for local and global decision-making, and practical implementation issues such as existing capacity and the political environment within a country. Previous studies have shown that while safety surveillance (pharmacovigilance) activities were established early in developing countries following the thalidomide disaster of the early 1960s, many LMICs did not prioritize it for various reasons, including limited access to medicines, poor funding, limited technical capacity, and low awareness of its importance in healthcare [33,34,35]. In 2008, the support for the establishment or strengthening of safety surveillance in LMICs got a boost from The Roll Back Malaria partnership, which issued guidelines requiring the inclusion of pharmacovigilance in the Global Fund and other related proposals . An analysis of 26 proposals submitted to the Global Fund after the guidelines were issued revealed that only 46% of proposals mentioned the establishment of pharmacovigilance systems. Subsequently, countries received guidelines and recommendations on how to include pharmacovigilance sections in their proposal for the Affordable Medicine Facility for malaria (AMFm) proposal from WHO and the Medicines for Malaria Venture (MMV) . Several other funding organizations now provide various levels of support for safety surveillance in LMICs .
Interviewees noted that several practical issues, including the prevalent political and bureaucratic environment, available technical and infrastructural resources within countries, and the countries targeted for the introduction of new or planned interventions, influenced the decision about countries to support. The challenges with the implementation of pharmacovigilance in LMICs have been well documented [26, 33, 38]. It has been noted that it is only when regular and sustainable budget allocation is provided by the government that meaningful and long-term progress can be achieved, as seen in India and China . Thus, it behooves governments in LMICs to prioritize not only vaccine coverage but also vaccine safety and to provide the enabling environment for robust safety surveillance to be carried out with government funding and with support from donor organizations.
4.1 Strengths and Limitations
A key strength of the study was drawing insights from key policymakers in the qualitative study. This allowed insights from qualitative evidence to explain some of the quantitative findings. Some of the key limitations of our study include the fact that most of the data were obtained from spontaneous reporting systems that rely on self-reporting, with the possibility of reporting bias resulting from heightened awareness about the safety of COVID-19 vaccines and uncertainty about the vaccines’ contribution to the reported events. This may have led to overreporting and overestimation of the burden of AEs. Also, ICSRs submitted to VigiBase do not typically contain certain information that allows some analysis to be done, such as the cause of death for fatal cases. Secondly, some regions did not have information on the doses administered (denominator) to support rate calculations. We have extrapolated the vaccine doses administered in those regions. These rates need to be interpreted with caution because AEs from spontaneous reporting systems and other reporting sources were combined in the numerator data, and the background rates of the reported AEs are unknown. In addition, the distribution of the different vaccine types could not be obtained for all regions, making it difficult to calculate the relative contribution of each vaccine to the reported AEs in this work. Another limitation of the study is that countries in the different regions have varying types of approved vaccines, vaccine distribution, and submission of ICSRs to VigiBase; hence, the comparison between regions needs to be interpreted with caution. Finally, for the qualitative study, the voices and perspectives of the PIPV implementers in recipient countries were not captured to understand what challenges they may be facing with safety surveillance and their proposals on how best to handle such challenges. Interview participants were selected based on the need to provide information-rich insights from the funder’s perspective, and we did not use a pre-selected theoretical framework to inform the wording and phrasing of the questions.
This study did not do a detailed review of the types and seriousness of the reported AEs by vaccine type. For Africa, there is a need to undertake such studies to fully understand the contribution of each vaccine to the profile of reported AEFIs.
Countries in Africa reported fewer AEFIs with COVID-19 vaccines in VigiBase relative to the RoW, with statistically significant differences in the reporting of key parameters, such as gender, age group, and serious reactions, that warrant further investigation. Funding organizations mostly do not have systematic approaches for deciding where funding may be allocated. Such decisions were influenced by country priorities, the perceived value added by the evidence generated by such systems to local and global decision-making, a desire to achieve equity in global vaccine coverage and safety through an effective global immunization strategy, and practical implementation issues. African countries and other countries in LMICs need robust safety surveillance systems to generate good data to inform decisions. Continuous support from national governments and donor/funding organizations will enhance equitable safety monitoring and Africa’s contribution to the global knowledge on COVID-19 vaccine safety in particular and the safety of other pharmaceutical interventions in general.
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We wish to acknowledge the contribution of Patrick C. Souverein of Utrecht University, who helped with extracting the VigiBase data that was used for the quantitative study. We acknowledge all the key policymakers from the different organizations that provided their rich perspectives during the interview that informed the qualitative component of this work. We use this opportunity to honor a pharmacovigilance hero, Sten Olsson, who was instrumental in the establishment of a pharmacovigilance system in many countries in Africa. He was a member of the team that developed the protocol for this work. VigiBase, the WHO global database of reported potential side effects of medicinal products, developed and maintained by Uppsala Monitoring Centre (UMC), is the source of the information used for the quantitative component of this study. The information comes from a variety of sources, and the probability that the suspected adverse effect is drug related is therefore not the same in all cases. The information provided in this study does not represent the opinion of the UMC or the WHO.
Comfort K. Ogar received funds from Harvard University and the Ronda Stryker and William Johnston MMSc Fellowship in Global Health Delivery to undertake the research work as part of her master’s thesis work. However, no funding support was received for the writing of the manuscript. The Global Health and Social Medicine (GHSM) department of Harvard Medical School (HMS) paid the fee for open access publication of this article.
Conflict of interest
Comfort K. Ogar received funds from Harvard University and the Ronda Stryker and William Johnston MMSc Fellowship in Global Health Delivery to undertake the research work as part of her master’s thesis work. No funding support was received for the writing of the manuscript. Jean Claude Mugunga, Hannah N. Gilbert, Jonathan Quick, Rick A. Vreman, and Aukje K. Mantel-Teeuwisse declare no conflict of interest.
The Harvard Institutional Review Board (IRB) determined that the quantitative study was not human subject research under 45 Code of Federal Regulations (CFR) 46.102(e), and additional IRB review was not required. The Nigerian Health Research and Ethics Committee (NHREC) also determined that the quantitative study meets the criteria for exemption under the National Code for Health Research Ethics and was exempt from the NHREC oversight. Because it involved secondary analyses of de-identified data, informed consent was not obtained. Similarly, the Harvard IRB determined that the qualitative study meets the criteria for exemption under the regulations found at 45 CFR 46.104(d) (2) and as such did not require further IRB review. The NHREC reviewed and approved the qualitative study and written informed consent with the following approval number NHREC/01/01/2007-03/08/2021.
Consent to participate
The quantitative study was secondary analyses of de-identified data and did not require informed consent. All participants in the qualitative study provided written informed consent to participate prior to the interview.
Consent for publication
Not applicable. No participant information is contained in the article, and therefore, consent for publication was not sought from participants.
Availability of data and materials
The datasets generated during and/or analyzed during the current study are not publicly available due to confidentiality requirements for handling reports of adverse reactions but may be made available from the corresponding author on reasonable request upon approval from the Uppsala Monitoring Centre (UMC).
CKO conceived the study and developed the protocol for the study. JCM, HNG, RAV, and AKM-T reviewed the protocol. CKO analyzed the data and drafted the manuscript. JCM, HNG, JQ, RAV, and AKM-T reviewed and approved the data analysis and manuscript. All authors read and approved the final version.
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Ogar, C.K., Quick, J., Gilbert, H.N. et al. Adverse Events to SARS-CoV-2 (COVID-19) Vaccines and Policy Considerations that Inform the Funding of Safety Surveillance in Low- and Middle-Income Countries: A Mixed Methods Study. Drug Saf 46, 357–370 (2023). https://doi.org/10.1007/s40264-023-01279-3