Lethal Respiratory Syncytial Virus in Zambia Is Sensitive to Long-acting Monoclonal Antibodies

To the Editors: Respiratory syncytial virus (RSV) is the most common cause of severe lower respiratory tract infection in the first 6 months of life with more than 97% of mortality occurring in low- and middle-income countries (LMICs).1 RSV mortality data from these geographic regions are limited, and if available, they mainly reflect in-hospital deaths resulting in an underestimate of the global burden of fatal RSV. Because of poor access to healthcare and low-quality healthcare, a sizable proportion of RSV-related deaths among infants in LMICs occurs in the community. For most infectious diseases, including influenza, genetic diversity of viruses affects mortality risk.2 Previously, we demonstrated that RSV is a major cause of overall infant mortality in Zambia.3 In the Zambia Pertussis and RSV Infant Mortality Estimation (ZPRIME) study, we measured facility and community RSV deaths among infants in Lusaka, Zambia through a systematic postmortem surveillance project at the University Teaching Hospital morgue. Between August 2017 and 2020, we found that RSV was present in 7% of all deceased infants and 32% of the RSV+ infant deaths occurred in the community. RSV deaths were concentrated in infants younger than 3 months and in infants from densely populated Lusaka townships. The key distinguishing feature of the ZPRIME study, compared with most studies that have measured the impact of RSV, is that all the participants were deceased, and therefore represented the most extreme of infection outcomes. We aimed to establish whether fatal RSV infection is related to specific RSV genetic sequences, or they could reflect nonvirologic factors such as the vulnerability of the infant population and/or ease of access to supportive medical care. To test the former hypothesis, we performed whole-genome sequencing as described previously4 on a subset of nasopharyngeal samples (n = 116) collected under the ZPRIME study resulting in 71 full-genome RSV sequences (success rate of 62.2%). Of these 71 sequences, 62 were subtyped RSV-A and 9 RSV-B. We complemented ZPRIME sequences with publicly available sequences from other African countries (South Africa and Kenya) and with not yet published sequences generated by the INFORM study from 17 countries globally.4 We inferred phylogenetic trees and the migration history for both subtypes in a Bayesian framework (Fig. 1).5,6FIGURE 1.: Phylogenetic reconstruction of ZPRIME postmortem sequences, and sequences from other African and non-African locations. Tips and internal branches are colored according to the most probable reconstructed ancestral state (location). The correspondence between the colors and locations is as in the legend.Here, we demonstrate that infants in Zambia are dying of RSV linked to diverse viral strains that are intermixed across the globe. Clusters of Zambian RSV sequences obtained from postmortem samples were identified throughout the phylogenetic trees, making it highly unlikely that there was a virologic factor involved in mortality (Fig. 1). In terms of global diversity of RSV, we found no single lineage specific for Zambia: Zambian sequences cluster with sequences from elsewhere. Zambian sequences are closely related to South African sequences and to a lesser extent to Kenyan sequences, indicating that RSV strains cocirculate within Africa. We therefore suggest that there does not appear to be anything distinct about the Zambian RSV strains per se compared with other African locations. We found limited local persistence of RSV within African countries, as sequences from African countries also cluster with those obtained at non-African locations. We did not find evidence of molecular nirsevimab resistance among the RSV strains from the ZPRIME study. The Ile206Met:Gln209Arg polymorphism in the nirsevimab binding site of RSV B became globally dominant with a prevalence of 1843 of 2800 (65.8%) among RSV B strains observed between 2015 and 2021.7 This RSV B polymorphism was also highly prevalent (7/9 sequences; 77.8%) in Zambia between 2017 and 2020. In sum, the newly obtained lineages suggest that Zambian RSV is typical of global RSV. Using analysis of viral genetics, we found no evidence supporting viral genetic risk to mortality. This finding is important for understanding the impact of RSV on infant deaths in Africa. RSV in Zambia seems entirely typical. Mortality may not be virus-related, but explained by the poor healthcare system, population (within-host diversity) or both. To date, host factors for RSV mortality have been poorly defined. Our virologic sequence study showed no substantial differences in RSV sequences from Zambia as compared with elsewhere. We therefore conclude that the fatal outcomes in these cases are not explained by genetic factors, but more likely nonvirologic factors, such as challenges in timely access to supportive care as we have documented previously,8 limited availability of supportive treatments at facilities or intrinsic vulnerabilities in the Zambian infant population. Mutation analysis of the nirsevimab binding site showed that currently available immunoprophylaxis strategies may be effective to prevent RSV mortality in LMICs. ACKNOWLEDGMENTS All 71 ZPRIME sequences reported in the manuscript were submitted to GISAID with the following accession numbers: hRSV/A/Zambia/Lusaka-4082/2018, hRSV/A/Zambia/Lusaka-1708/2018, hRSV/A/Zambia/Lusaka-1925/2018, hRSV/A/Zambia/Lusaka-3230/2019, hRSV/A/Zambia/Lusaka-3099/2018, hRSV/A/Zambia/Lusaka-2617/2019, hRSV/A/Zambia/Lusaka-1210/2019, hRSV/A/Zambia/Lusaka-2615/2019, hRSV/A/Zambia/Lusaka-3935/2018, hRSV/A/Zambia/Lusaka-1937/2018, hRSV/A/Zambia/Lusaka-4073/2018, hRSV/A/Zambia/Lusaka-1948/2018, hRSV/A/Zambia/Lusaka-4520/2019, hRSV/A/Zambia/Lusaka-4593/2018, hRSV/A/Zambia/Lusaka-1129/2018, hRSV/B/Zambia/Lusaka-5070/2019, hRSV/A/Zambia/Lusaka-2141/2019, hRSV/A/Zambia/Lusaka-3103/2018, hRSV/A/Zambia/Lusaka-2057/2018, hRSV/A/Zambia/Lusaka-2133/2019, hRSV/A/Zambia/Lusaka-4089/2018, hRSV/A/Zambia/Lusaka-1983/2018, hRSV/A/Zambia/Lusaka-3117/2018, hRSV/A/Zambia/Lusaka-2557/2019, hRSV/A/Zambia/Lusaka-1103/2018, hRSV/A/Zambia/Lusaka-3922/2018, hRSV/A/Zambia/Lusaka-3924/2018, hRSV/A/Zambia/Lusaka-2074/2018, hRSV/B/Zambia/Lusaka-3221/2019, hRSV/A/Zambia/Lusaka-3195/2019, hRSV/B/Zambia/Lusaka-1207/2019, hRSV/A/Zambia/Lusaka-1932/2018, hRSV/A/Zambia/Lusaka-3145/2018, hRSV/A/Zambia/Lusaka-1122/2018, hRSV/A/Zambia/Lusaka-3239/2019, hRSV/A/Zambia/Lusaka-3204/2019, hRSV/A/Zambia/Lusaka-3215/2019, hRSV/B/Zambia/Lusaka-5051/2019, hRSV/A/Zambia/Lusaka-3934/2018, hRSV/A/Zambia/Lusaka-4508/2018, hRSV/B/Zambia/Lusaka-1212/2019, hRSV/A/Zambia/Lusaka-3939/2018, hRSV/A/Zambia/Lusaka-3938/2018, hRSV/B/Zambia/Lusaka-3219/2019, hRSV/A/Zambia/Lusaka-1970/2018, hRSV/A/Zambia/Lusaka-1139/2018, hRSV/A/Zambia/Lusaka-4654/2019, hRSV/A/Zambia/Lusaka-3210/2019, hRSV/A/Zambia/Lusaka-1238/2019, hRSV/A/Zambia/Lusaka-1953/2018, hRSV/A/Zambia/Lusaka-1119/2018, hRSV/A/Zambia/Lusaka-4627/2018, hRSV/A/Zambia/Lusaka-4113/2019, hRSV/A/Zambia/Lusaka-1112/2018, hRSV/B/Zambia/Lusaka-1201/2019, hRSV/A/Zambia/Lusaka-4652/2019, hRSV/B/Zambia/Lusaka-3224/2019, hRSV/B/Zambia/Lusaka-3209/2019, hRSV/A/Zambia/Lusaka-1218/2019, hRSV/A/Zambia/Lusaka-4116/2019, hRSV/A/Zambia/Lusaka-3923/2018, hRSV/A/Zambia/Lusaka-1704/2018, hRSV/A/Zambia/Lusaka-1117/2018, hRSV/A/Zambia/Lusaka-5034/2019, hRSV/A/Zambia/Lusaka-1105/2018, hRSV/A/Zambia/Lusaka-1936/2018, hRSV/A/Zambia/Lusaka-1126/2018, hRSV/A/Zambia/Lusaka-4573/2018, hRSV/A/Zambia/Lusaka-1200/2019, hRSV/A/Zambia/Lusaka-3102/2018, hRSV/A/Zambia/Lusaka-1197/2019.