Influenza surveillance capacity improvements in Africa during 2011‐2017

Abstract Background Influenza surveillance helps time prevention and control interventions especially where complex seasonal patterns exist. We assessed influenza surveillance sustainability in Africa where influenza activity varies and external funds for surveillance have decreased. Methods We surveyed African Network for Influenza Surveillance and Epidemiology (ANISE) countries about 2011‐2017 surveillance system characteristics. Data were summarized with descriptive statistics and analyzed with univariate and multivariable analyses to quantify sustained or expanded influenza surveillance capacity in Africa. Results Eighteen (75%) of 24 ANISE members participated in the survey; their cumulative population of 710 751 471 represent 56% of Africa's total population. All 18 countries scored a mean 95% on WHO laboratory quality assurance panels. The number of samples collected from severe acute respiratory infection case‐patients remained consistent between 2011 and 2017 (13 823 vs 13 674 respectively) but decreased by 12% for influenza‐like illness case‐patients (16 210 vs 14 477). Nine (50%) gained capacity to lineage‐type influenza B. The number of countries reporting each week to WHO FluNet increased from 15 (83%) in 2011 to 17 (94%) in 2017. Conclusions Despite declines in external surveillance funding, ANISE countries gained additional laboratory testing capacity and continued influenza testing and reporting to WHO. These gains represent important achievements toward sustainable surveillance and epidemic/pandemic preparedness.


| INTRODUC TI ON
Although sentinel surveillance in African countries for viral respiratory infections such as influenza is important for prevention and control, funding for such activities has steadily decreased making its sustainability uncertain. Africa has a higher influenza-associated mortality burden than other regions. This is important as few African countries routinely vaccinate against influenza and or treat severe respiratory illnesses empirically with antivirals during the influenza seasons. 1,2 Much of Africa's population is low and middle income and have substantial prevalence of underlying medical conditions [3][4][5] and limited access to health care, increasing the risk of severe complications as a result of influenza illness. 6 Only 3 of Africa's 54 countries have government-subsidized seasonal influenza vaccination programs. 7 Nevertheless, more African countries have influenza vaccines available through the private sector, are evaluating the potential value of influenza vaccination, [8][9][10] or are introducing publicly available influenza vaccines among key risk groups. In addition to nascent influenza vaccination programs, some countries in Africa also treat severe influenza illnesses during influenza epidemics and pandemics with empiric antivirals, and/or deploy non-pharmaceutical interventions to prevent contagion during epidemics (eg, respiratory hygiene, social distancing, and hand washing campaigns). 5,[11][12][13] The impact of these interventions is optimized by their timely deployment immediately before the anticipated start of epidemics.
Given the value of influenza surveillance for seasonal epidemic and pandemic mitigation, international agencies and governments provided substantial financial and technical resources to build global influenza surveillance capacity at the turn of the century. 14 Much investment in capacity-building in the early 2000s occurred in Africa which had a dearth of surveillance and a disproportionate disease burden. As a result, influenza surveillance rapidly improved throughout Africa during the peri-pandemic period. The strengthening of surveillance allowed countries to better define their epidemic periods and, as a secondary benefit, estimate the burden of respiratory illnesses attributable to influenza. [15][16][17][18][19][20][21] Investments were higher during the initial years of grants to encourage rapid capacity-building and operationalization of surveillance, resources then tapered off with countries assuming greater technical and The rapid investment and gradual divestiture strategy rapidly built sustainable influenza surveillance capacity in the Americas, 14 but it is unclear if this strategy has also been effective in Africa.
The African Network for Influenza Surveillance and Epidemiology (ANISE) is a regional consortium of subject matter experts seeking to improve surveillance in Africa. Most African countries who are members of ANISE have previously used their influenza-like illness (ILI) and/or severe acute respiratory infection (SARI) or other respiratory disease surveillance systems to identify and test for the Middle East respiratory syndrome (MERS) 22 and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Indeed, these platforms have been critical to the 2019 coronavirus disease (COVID-19) pandemic response in Africa. 23,24 Given the importance of these platforms, we sought to evaluate influenza sentinel surveillance function in Africa from 2011 to 2017, 5 after external funding to surveillance in Africa started to decrease and determine if initial investments in capacity-building led to sustainable influenza surveillance.

| Data collection
We used a standardized survey to gather information about sentinel surveillance practices, real-time reverse transcription polymerase chain reaction (rRT-PCR) capacity, the number of samples tested, and the number positive for influenza by week and age group during 2011-2017. Influenza type, subtype, and lineage data were collected, if available. To explore whether influenza surveillance networks had expanded or contracted during the study period, we also gathered information about the type of surveillance conducted (ie, for ILI and/ or SARI), and number of active sites. We assessed whether the case definitions reported by the survey matched WHO-recommended ILI and SARI case definitions. 26 Data were collected through the InSAFRO survey about national surveillance operational costs and funding sources. We reviewed reported avenues for regular dissemination of surveillance data in country to determine whether the generated influenza surveillance data were used to inform influenza prevention and control measures (eg, launching risk communication and vaccination campaigns). Finally, we surveyed participants about national vaccine policies or guidelines that could benefit from influenza surveillance.

| Additional data collection
We also gathered information about influenza test results reported to the GISRS platform FluNet [40] and about samples shared with WHO Collaborating Centers (CCs). We reviewed published and unpublished burden of disease estimates solely to estimate the number from InSAFRO countries (ie, not to extract findings for a meta-analysis); this review was conducted until September 2019. We summarized findings by World Bank income classification and population size 27 to estimate the representativeness of samples collected and tested.

| Data analyses
To describe surveillance capacity during 2011-2017, we summarized the number of sentinel sites and rRT-PCR throughput capacity for laboratory testing by country. The collection of potential risk factors for SARI and in-hospital deaths were also noted. We estimated the relationship between annual rates of samples tested and positives by WHO transmission zone. We repeated this for each country during 7 years of surveillance using a generalized estimating equation method with repeated-measures Poisson regression where the dependent variables were counts of influenza-positive detections and samples tested for each year of the study and the independent variable WHO transmission zone. 28 We explored the association between surveillance funding source and World Bank income classification status using Fisher's exact test to determine if there were non-random associations between income classification and funding source (eg CDC, WHO, or Government) as categorical variables.
We also plotted the number of samples tested and the proportion of influenza detections among ILI and SARI case-patients during the 7-year surveillance period by age group to determine changes in the amount of testing by age group. We used a linear regression to identify potential trends in the number of influenza viruses shared with WHO CCs and samples reported to FluNet over time. Lastly, we used Mann-Whitney Rank Sum test to explore whether countries that used influenza vaccines in the private or public sector were more likely to report a greater number of influenza tests results to  (27) 1096 (35) 637 (29) Southern South Africa b,c,e 56 717 156 (5) 1984 Y 89 3 8 9967 (9) 27 191 (4) 5308 (5) Western Côte d'Ivoire b,c,e 24 294 750 (2) 2007 Y 91 14 11 11 048 (10) 2927 (5) 1996 (9) Western

| Ethics and funding
This project was deemed a program evaluation and received a nonresearch determination from the CDC IRB because it does not use data from human subjects; its primary intent was to determine the fitness and capacity of influenza surveillance to serve participating countries. The data collection forms and templates were reviewed and approved by the ANISE working group. Collaborating institutions received official invitation letters requesting information about their surveillance systems. This project was supported by the ANISE executive committee and funded by CDC.   Countries reported that influenza surveillance cost approximately between $10 000 and $1 267 280 to operate each year F I G U R E 1 Countries participating in the influenza surveillance in Africa analysis (median $105 000). All 18 countries paid for surveillance with funds from multiple agencies (Figures 2 and 3). We found no associations between the type of external funding and World Bank income classification. Seven (39%) of the 18 countries conducted influenza surveillance as part of an integrated disease surveillance system for improved detection and response to leading causes of illness.  to influenza that could be used to explore the value proposition of influenza vaccines. 4,[15][16][17]20,21,30

| Surveillance and laboratory capacity
Our results suggest that following substantial investment in capacity-building at the turn of the millennium, most of the 18 African All surveyed countries had the capacity to test influenza specimens through rRT-PCR, which helped them to maintain situational awareness about respiratory viruses in their respective countries. Although the number of sentinel surveillance sites has not significantly increased from 2012, possibly in an effort to improve the cost-benefit of surveillance, there was an overall increase in sampling and testing. Sampling for SARI respiratory increased especially among children aged 0-4 years ( Figure S2).
The overall increase in SARI sampling, which was accompanied by a modest decrease in ILI sampling, might be attributed to an emphasis by the global community to strengthen severe respiratory illnesses surveillance to compensate for the perceived shortcomings of surveillance to track severe illnesses during the 2009 pandemic. 31,32

| Participation in GISRS and WHO CCs
Investment in surveillance capacity-building resulted in sustained reporting of virus activity to GISRS and shipment of specimens to WHO CCs, even after a 37% decrease in external funding for such activities. All countries contributed influenza viruses to one or more WHO CCs during the northern and southern hemisphere Vaccine Composition Meeting for vaccine candidate virus selection.
Although specimen testing increased among participating countries, the number of positive viruses shared with WHO CCs by transmission zones remained similar throughout the study period ( Figure S5).
Although we suspect additional specimens were not requested by the CCs because of limitations in the number that CC's can characterize. There may be value in setting benchmarks for the minimum and maximum number of influenza specimens collected within the beginning, middle, and end of epidemics that should be shipped quarterly to WHO CCs assuming year-round transmission. Such benchmarks might allow countries to ensure that they share timely specimens and maximize the chances that influenza viruses identified within their country will be adequately represented in vaccine formulations.
In addition to demonstrating sustained or increased testing capacity during 2011-2017, our survey showcases the increase in the number of NICs in Africa and their newly attained ability to lineage-type influenza B. NICs are critical to the sustainability of surveillance because they orchestrate laboratory surveillance within countries, provide support to subnational laboratories, and liaise with WHO and its CCs. NICs do proficiency testing for subnational laboratories, test clinical specimens for influenza, identify and further characterize viruses, and report findings to WHO through FluMart. NICs also collect specimens for shipment to CCs either emergently, when they identify what might be novel viruses, or quarterly to inform vaccine strains selection. This is evident during the current COVID-19 pandemic where NICs are the underpinning for the rollout of testing for SARs-CoV-2. 23,24,33 In 2018, the WHO revised the Terms of Reference (TOR) for NIC status to exclude the requirements for national laboratories to isolate influenza viruses. This shift in TOR recognized that some CCs prefer that countries send influenza-positive specimens for rapid sequencing first rather than delay shipment with virus isolation attempts. In Africa, virus isolation requirements frequently held back national laboratories from achieving WHO NIC designation; we anticipate that more countries in Africa will now be able to attain WHO NIC designation because of the relaxed TOR. Despite notable national and institutional commitments, surveillance systems in Africa still rely largely on external funding to sustain or increase surveillance capacity. All countries were also beneficiaries of the CDC-funded International Reagent Resource, which provided registered countries with the reagents for the surveillance of novel and emerging influenza strains at no cost. In addition, WHO, Institut Pasteur, and national governments supported influenza surveillance and regional capacity strengthening to respond to outbreaks and for pandemic preparedness.

| Vaccines and policy
Seasonal influenza vaccines are available in African countries, however public sector access remains limited. Influenza vaccines were available in the private and public sector in two-thirds of the 18 surveyed countries and, although more than a third had influenza disease burden estimates, less than one in five countries had publicly available national vaccine guidelines or policies. In countries using influenza vaccines, these were typically available in pediatric health centers, private pharmacies, and embassies except for two countries (South Africa and Madagascar) where influenza vaccines were licensed, offered routinely at the point of care, and recommended in the public sector. In South Africa, for example, free seasonal influenza vaccines were available in all public primary care facilities with a limited stock of approximately 1 000 000 doses for use among persons at high risk of influenza complications. Of note, countries that used influenza vaccines in the private sector reported, on average, a higher number of samples to WHO FluNet.
Our survey suggests that a disproportionally high percent of specimens from InSAFRO countries came from children aged <5 years. Although 16% of the 2019 census population for countries is aged <5 years, children aged <5 years represented 61% of ILI and 53% of SARI specimens. Our finding is consistent with that of other studies in Africa including Zambia where 60-80% of SARI samples were from young children. 21 The large percent of children which comprise surveillance case-patients might reflect underlying rates of severe respiratory illness among those in the extremes of age and health utilization patterns that focus scarce resource on children rather than older adults as noted in a handful of health utilization surveys. 17,20,21,30,34,35 Additional evaluations are needed to determine if the proportion of samples obtained from different age groups is representative of those who seek care at sentinel sites.
Such evaluations might be useful because representative sampling was not included as a formal milestone for evaluation in CDC funding opportunity applications.

| Limitations
The InSAFRO analyses were limited to surveillance data from 18 out of 54 WHO Member States in Africa. Nevertheless, these 18 countries comprised half of Africa's population and our findings might be generalizable to additional countries in Africa. We did not comprehensively quantify external funding countries received for surveillance. InSAFRO countries reported 21% more respiratory samples results to WHO FluNet than they reported to our survey, possibly because our survey allowed participants to report results once while FluNet allows countries to update backlogged results at any given time. We also did not enumerate the number of pediatric-focused health facilities in order quantify the proportion of specimens from clients aged <5 that were collected from pediatric inpatient or outpatient health facilities. We did not explore exact amounts countries were awarded versus amounts spent in their cooperative agreement funds. Finally, our survey was not designed to explore how countries used surveillance findings for public health action.

| CON CLUS ION
Our InSAFRO survey suggests that investments in capacity-building at the turn of the millennium led to sustainable influenza surveillance among African countries. Despite substantial decreases in external funding, countries tested more respiratory samples, especially among children with SARI, and reported to FluNet more than ever before. InSAFRO countries have continued to share samples with WHO CCs and to meaningfully participate in GISRS. During the study period, several countries successfully achieved WHO NIC designation, and some gained the ability to lineage test influenza B. These gains represent important achievements in seasonal and pandemic influenza preparedness. It will be important to continue to monitor capacity in the region and to observe if more countries use their gains in surveillance to strengthen vaccine programs and other respiratory virus mitigation and control measures.

ACK N OWLED G EM ENTS
We thank all members of the ANISE Network Working Group and partner countries who contributed national ILI and SARI influenza surveillance data to this survey. We thank Ann Moen, April Vance, and Mary-Ann Hall for enriching the discussion for the development of this manuscript. None of the authors have any conflicts of interest to declare.

S U PP O RTI N G I N FO R M ATI O N
Additional supporting information may be found online in the Supporting Information section.