Among key findings, we found that patterns of wave propagation throughout the region were similar across almost all country waves. In the absence of a representative regional surveillance system for influenza-like illness, surveillance data from South Africa, where waves were first detected, provided an early warning signal for other countries in the region. Although per person volume of testing increased over time in southern Africa, it remained low compared with resource-rich countries and differed among countries, limiting the ability to compare reported incidence and mortality. Genomic sequencing in the region was limited outside of South Africa. In most countries, reported percentage positivity, incidence rates, mortality rates, and CFRs increased across waves, partly caused by the emergence of more transmissible variants. Stringent PHSM implementation declined over successive waves, and vaccine coverage was low.

Because South Africa accounted for >30% of cases in Africa, average wave patterns were similar between southern Africa and Africa as a whole but with notable regional and intercountry variations (6). Kenya, in eastern Africa, experienced second and third waves before southern Africa. In southern Africa, all waves followed a similar regional pattern: waves were first detected in South Africa, then throughout the remaining interconnected countries an average of 7.2 weeks later. This pattern was less obvious for Angola, where the second wave started 20 weeks after South Africa (Appendix Table 1). This pattern likely reflects greater testing capacity in South Africa, more sensitive surveillance, and possibly mobility characteristics in the region because South Africa is an international transportation hub. According to phylogenetic analysis, South Africa was determined to be the source of SARS-CoV-2 cases imported to the rest of the region during the first and second pandemic waves (17). Awareness of this pattern is critical for future mitigation efforts; pretravel testing and ongoing sentinel surveillance might be critical for detecting cross-border transmission early, and pandemic surveillance and reporting in South Africa can serve as an early warning signal for countries with more limited testing capacity. However, a regional, representative, surveillance system for influenza-like illness and severe acute respiratory illness could improve regional detection and response systems.

Although weekly population-level numbers of tests increased, testing per case, an indicator of sufficient coverage in high-transmission periods, decreased across waves, and the region never achieved the WHO-recommended target of 1,000 tests/1 million persons (18). The region’s average testing volume per person was low compared with resource-rich countries: ≈240 tests/1 million persons/day in southern Africa versus >3,000 tests/1 million/day in the United States (4). Even Namibia and South Africa, despite relatively higher testing volumes, were below the WHO target for testing. This target might be unreachable for most countries in this region unless test accessibility for the general population is substantially improved. Increasing availability and feasibility of COVID-19 self-tests, as recommended by Africa CDC (19), might increase testing and improve public health mitigation efforts (20,21).

In this resource-constrained region, testing volumes should be expanded on the basis of need and be designed to collect data to address key objectives for public health response. These data include diagnosing admissions, classifying excess deaths because of COVID-19, defining the timing of pandemic waves, monitoring circulating variants, and informing guidance for work, school, and social engagements. Data gathered from serosurveillance and postmortem activities might also help address these objectives (3,4,22).

Our ability to directly compare SARS-CoV-2 case and death counts in the region using publicly available data was limited by changes over time in test types and availability, low likelihood of diagnosis (4), and various and changing testing strategies. Sustaining COVID-19 sentinel surveillance systems in the community and among high-risk populations (23), including through targeted use of antigen rapid diagnostic tests (24), and improving standard reporting throughout the region to ensure appropriate local epidemiologic evaluations and responses (25), could be considered. These data-gathering systems could be coordinated through a regional body such as the recently established Africa CDC Southern Africa Regional Collaborating Centre (26).

Genomic sequencing varied across countries and was limited outside South Africa. Low sequencing limits detection of new VOCs, posing regional and global health security risks. Africa CDC and WHO are strengthening genomic surveillance by establishing a continentwide laboratory network, leveraging existing surveillance systems, to better detect variant evolution (27). To improve sequencing of SARS-CoV-2 and other endemic and epidemic pathogens, systematic in-country genomic surveillance could be built and sustained in the region by adopting sequencing targets such as weekly targets based on incidence and estimated prevalence of variants in line with Africa CDC guidelines (28–30). In southern Africa, Beta variant was predominant in the second wave and Delta in the third.

Across the region, the third COVID-19 wave had the highest 7-day average percentage positivity, daily cases, deaths per 1 million population, and CFR. Increases in reported incidence and mortality at a time of increasing percentage positivity occurred at least partly because of the emergence of more transmissible variants across waves. However, the connection between high testing volume and reported incidence and mortality rates per person in upper-middle-income countries Namibia and South Africa might reflect better testing capacity contributing to improved accuracy of identifying cases and classifying cause of death, leading to higher reported overall incidence and mortality rates (31).

Neither emergence of more transmissible variants nor improved testing capacity can fully explain the increase in CFR over time, an observation that has been previously reported for Africa (32–34). Possible explanations for this increase include increased strain on limited critical care capacity as transmission and hospitalizations increased (6,34,35); health systems with minimal critical care resources are not optimized for managing critically ill COVID-19 cases. A recent prospective cohort analysis found that mortality among critically ill hospitalized patients was 48.2% in Africa, higher than the estimated 31.5% global average (32,34). Other explanations might include delays in healthcare-seeking behavior by patients, improved differential testing and reporting (i.e., relatively fewer tests among persons who are not ill but more among very ill persons), improvements in classifying COVID-19–related deaths, and declining ability to protect vulnerable populations from SARS-CoV-2 exposure. However, increased CFR in the region suggests the need for improved health systems and access to newer therapeutics for high-risk patients, such as antivirals molnupiravir (36) and nirmatrelvir (37).

The increased incidence, mortality, and CFR during the third wave were not universal across countries. Lesotho reported highest average incidence rates during its second wave, and Lesotho and South Africa reported highest average mortality rates during the second waves. Eswatini also reported a lower CFR in its third wave than in its second. Possible explanations for those patterns include development of natural immunity to severe disease (4), improved outbreak response and service delivery (38), or incomplete data analysis because the third wave was not yet complete when we collected data.

Declining stringency in adherence to PHSMs in the region likely occurred as governments acknowledged sociopolitical, cultural, and economic context, rather than just epidemiologic data, to determine appropriate restrictions (39). Decreasing acceptance of and adherence to PHSMs has been observed in 4 countries in the region, in part because of negative effects on livelihoods and lack of access to health services (23). To improve adherence, PHSMs could be introduced, adapted, and lifted based on situational assessments in each country and considering community feedback (25,40,41). Given likely challenges in implementing and enforcing stringent PHSMs in the future, policymakers could consider targeting new measures towards persons at highest risk for severe disease.

On average, 8.1% of the population in the region was fully vaccinated as of September 19, 2021, compared with 46.7 in Morocco, 53.9 in the United States, and 63.6 in Israel (5). Vaccine coverage in southern Africa faced challenges including low domestic manufacturing capacity, donations of vaccines near their expiration dates, vaccine hoarding by high-income countries, and low vaccine uptake (42,43), highlighting the need to expand equitable access to vaccines and regional vaccine manufacturing capacity (44). Considering the WHO-recommended target that 70% of the population be fully vaccinated by mid-2022 might be unrealistic for the region (45) and likely high SARS-CoV-2 seropositivity (4), vaccination campaigns targeting populations in the region at highest risk for death, such as persons who are elderly or have chronic underlying conditions (46), might be effective in reducing severe disease and emergence of VOCs (47). To expand access to COVID-19 vaccinations, particularly for immunosuppressed persons, some countries in Africa (e.g., Zambia) have integrated COVID-19 vaccination services into existing health delivery platforms and clinics (e.g., HIV clinics); bringing vaccine access closer to home might aid in uptake (48).

We used publicly available datasets, each with data quality challenges. The OWID dataset missed some daily reports, so we requested coauthor data validation from country officials and Africa CDC to ensure reliability of the data. However, missing data from OWID limited our ability to compare pandemic waves between countries, especially those outside South Africa. OWID uses date reported, rather than specimen collection date, meaning that waves might have appeared to begin and end later in countries with time lags between testing and reporting. We assumed standard WHO definitions were used for reporting COVID-19 cases and deaths in the OWID dataset. We did not account for changes in test availability and testing strategies over time, which limited consideration of potential differences in those indicators among countries. The GISAID dataset varied in representativeness because some countries submitted very limited specimens, so we reported genomic surveillance results at a country level to highlight variability among countries. The OxCGRT dataset includes safety and control measures mandated by governments but not the extent of adherence to the measures, which might better correlate with transmission. Regional trends might be more influenced by data reported by an individual country, particularly South Africa, which provided most OWID and GISAID data. Our data were also extracted while the third wave was ongoing in the region, although it was declining except in Angola, where the third wave had not yet peaked by September 19, 2021. Despite those limitations, by soliciting data reviews from representatives for each country, reporting results at a country level, and computing regional indicators averaging country rates adjusted for population size and daily variation, we have compiled a reasonable description of the pandemic situation across southern Africa.

By September 19, 2021, southern Africa had experienced 3 waves of COVID-19, almost all first detected in South Africa, and with successively higher reported percentages of positivity, incidence, mortality, and CFRs. Increased incidence and mortality could be partly explained by the emergence of more transmissible SARS-CoV-2 variants and improved testing capacity and surveillance. Increasing CFRs warrants further research and highlights opportunities for strengthening health systems and increasing access to feasible therapeutics for high-risk persons. Testing volume increased across waves but varied by country and remained low compared with resource-rich countries. Genomic surveillance capacity was limited, although South Africa played a key role in supporting other countries. Stringent PHSM implementation declined over time, indicating a decrease in feasibility. Vaccination coverage remained very low; scale-up, especially among high-risk persons, should be considered. Coordinated regional solutions could be considered to strengthen and sustain sentinel surveillance systems, genomic surveillance capacity, risk-based vaccination, and tailored public health mitigation to better detect, prevent, and reduce the severity of future COVID-19 waves and other outbreaks in southern Africa.