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).

Table 1 Distribution of overall adverse events and estimated adverse events per 1 million administered doses by World Health Organization (WHO) regionTable 2 Comparison of key parameters between adverse events (AEs) from the African region and the rest of the world (RoW)

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).

Table 3 Distribution of reported adverse events (AEs) by vaccine type and most frequently associated system organ class (SOC) after omitting missing variables and vaccines with unclassifiable namesTable 4 Estimated adverse events (AEs) per 1 million doses by vaccine type for the World Health Organization (WHO) AFRO Region

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.

Table 5 Joint display of convergent data from quantitative and qualitative findings3.4.1 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)