Extensive SARS-CoV-2 spread in Sierra Leone despite few reported cases and illness

One of the enduring mysteries of the COVID-19 pandemic has been why sub-Saharan Africa, home to more than a billion people, recorded fewer than 2 percent of the world’s confirmed SARS-CoV-2 cases and deaths, even as hospitals in North America and Europe overflowed. A new longitudinal study from eastern Sierra Leone offers one of the most detailed answers yet: the virus was circulating widely in the region by early 2022, infecting the vast majority of study participants, yet almost nobody became visibly ill. The findings, published in Immunity, Inflammation and Disease, suggest that pre-existing antibody immunity—possibly arising from exposure to common cold coronaviruses or an as-yet unidentified coronavirus circulating in West Africa—may have silently blunted the pandemic’s impact in this corner of the continent.

The research, led by scientists at Tulane University in collaboration with Sierra Leone’s Kenema Government Hospital, followed 306 participants drawn from an established cohort of viral hemorrhagic fever survivors and their household contacts in Eastern Province. Crucially, the team had access to banked blood samples collected before the pandemic ever began, in mid-2017 and early 2019, allowing them to compare the immune landscape before and after SARS-CoV-2 arrived. They collected additional samples in March 2022, just before a national vaccination campaign reached the region, and again one month after participants received the Johnson & Johnson COVID-19 vaccine. The result is a rare four-timepoint immunological portrait of a population that, on paper, barely experienced the pandemic.

Sierra Leone’s official statistics are striking. As of October 2024, the West African nation of roughly 8.8 million people had reported just 7,985 cumulative COVID-19 cases and 125 deaths—a case fatality rate of 1.45 per 100,000 population. Early skeptics attributed these figures to weak surveillance and inadequate testing, but front-line health workers in the country reported that tests were in fact available and that hospitals were never inundated with severe respiratory illness, in stark contrast to the scenes that played out in wealthier nations. The new study set out to determine whether the virus truly was absent, or whether it was spreading invisibly beneath the official numbers.

The laboratory work centered on measuring IgG antibodies against three SARS-CoV-2 proteins—the spike (S) protein, the nucleoprotein (N), and the receptor binding domain (RBD)—using a multiplex electrochemiluminescence platform from Meso Scale Discovery, alongside antibodies against the four seasonal human coronaviruses (229E, OC43, NL63, and HKU1) and the emerging coronaviruses SARS-CoV-1 and MERS-CoV. Seropositivity cutoffs were set by the manufacturer at 5,000 AU/mL for nucleocapsid, 528 AU/mL for RBD, and approximately 2,000 AU/mL for spike. What the team found before the pandemic was remarkable: 16 to 21 percent of Sierra Leonean samples collected in 2017 and 2019 already showed reactivity to the SARS-CoV-2 nucleoprotein, roughly 31 percent were seropositive for the RBD, and a smaller but notable 3.3 to 3.4 percent reacted to the spike protein. By comparison, pre-pandemic US control samples—collected between 2013 and 2016 as part of the Bogalusa Heart Study in Louisiana—showed seropositivity of only 5.7 percent for N, 8.3 percent for RBD, and 1.0 percent for spike. The differences between the two populations were highly statistically significant.

Then came the pandemic itself. By March 2022, seropositivity in the Sierra Leonean cohort had exploded to 81.1 percent for nucleocapsid, 93.1 percent for RBD, and 92.2 percent for spike—an unmistakable signal that SARS-CoV-2 had swept through the community despite the near-total absence of reported cases in the region. Yet when participants were surveyed, only five individuals out of 306—1.6 percent—reported any respiratory symptoms consistent with COVID-19 since the pandemic began, and only one of those reported a positive test. The virus was everywhere; the disease was almost nowhere to be seen.

To confirm that these antibody signals represented genuine infection rather than mere cross-reactivity, the researchers deployed a pseudovirus neutralization assay. In this system, lentiviral particles engineered to display the SARS-CoV-2 spike protein of the Wuhan-1 strain carrying the D614G mutation were incubated with heat-inactivated serum and then used to infect ACE2-expressing CHO cells. Because the pseudovirus carries only the SARS-CoV-2 glycoprotein—a feature unique to SARS-CoV-2 and not shared with seasonal coronaviruses—any neutralizing activity detected against it must reflect true SARS-CoV-2-specific antibodies. The results were definitive: while almost no pre-pandemic samples could neutralize the virus, roughly 90 percent of intra-pandemic samples showed moderate or strong neutralizing capacity, with 73.6 percent classified as strong neutralizers, blocking more than 80 percent of pseudovirus activity at a 1:50 serum dilution. Neutralization levels in March 2022 were significantly higher than at either pre-pandemic timepoint, comparable to the robust responses documented in natural infections elsewhere in the world.

The pre-existing immunity story grew more intriguing when the team compared seasonal coronavirus profiles between the two populations. Antibodies to all four seasonal HCoVs fluctuated over time in Sierra Leone, consistent with seasonal circulation, but overall levels were broadly similar to those in the US cohort. More striking was the pattern for the emerging coronaviruses: Sierra Leonean samples from every pre-pandemic timepoint showed significantly higher mean antibody concentrations against MERS-CoV and SARS-CoV-1 spike proteins than the US controls. This, combined with the elevated reactivity to SARS-CoV-2 proteins, raises the tantalizing possibility that a novel, previously unidentified coronavirus may have been circulating in Sierra Leone before COVID-19, priming the population’s immune systems in ways that crossed over to SARS-CoV-2. The researchers also observed a cross-boosting effect: after SARS-CoV-2 vaccination, antibody concentrations against OC43, MERS-CoV, and SARS-CoV-1 all rose significantly, consistent with known antigenic cross-reactivity among coronaviruses.

Importantly, the study does not claim that pre-existing immunity prevented infection. Indeed, the data show it did not—exposure was nearly universal by 2022 regardless of pre-pandemic antibody status, and baseline seropositivity to any SARS-CoV-2 protein did not predict higher antibody concentrations or better neutralization afterward. What the pre-existing immunity may have done instead is soften the blow. With nearly the entire cohort reporting no respiratory illness whatsoever despite serological evidence of infection, the authors argue that cross-reactive humoral immunity plausibly reduced disease severity, which in turn reduced care-seeking and testing, creating the illusion that the virus was absent. Antibodies, after all, do more than neutralize; they recruit natural killer cells, neutrophils, monocytes, and the complement system through their Fc regions, and the team notes that some seropositive individuals who lacked neutralizing capacity may still have possessed other functional antibody activities, such as antibody-dependent cellular cytotoxicity, which follow-up studies are now exploring.

The work builds on earlier findings by the same group, who in 2020 reported that 30 to 80 percent of pre-pandemic Sierra Leonean sera reacted to the nucleoproteins of common cold coronaviruses and showed elevated reactivity to SARS-CoV-2, SARS-CoV, and MERS-CoV compared with US controls. The new study validates those results in a larger cohort with a longitudinal design, addressing a key shortcoming of much of the existing literature, in which pre-pandemic and pandemic samples came from different individuals or were tested with inconsistent assays. Similar pre-existing cross-reactivity has been reported in other parts of sub-Saharan Africa and in Vietnam, adding to a growing body of evidence that the “puzzle” of Africa’s mild pandemic is not a puzzle of missing data but a genuine immunological phenomenon.

There are caveats. The cohort consisted of Ebola and Lassa fever survivors and their household contacts, a convenience sample that could introduce selection bias, although a subanalysis found that survivors and contacts had similar antibody concentrations and neutralization profiles. And because symptomatic COVID-19 was so vanishingly rare in the cohort, the researchers could not directly measure the protective effect of pre-existing antibodies against disease severity. The authors point to host genetics as another likely contributor: a recent large study identified the HLA-B*15:01 allele as protective against symptomatic COVID-19 through pre-existing T-cell responses, and HLA distributions in Sierra Leone remain poorly characterized. Planned studies comparing HLA types between symptomatic and asymptomatic individuals, and investigations of cellular immunity in cohorts with cryopreserved pre-pandemic cells, should help complete the picture.

For now, the Sierra Leone findings reshape the narrative of the pandemic in Africa. The virus did not spare the region—it simply moved through it with far less carnage, hidden by immune systems that had, through encounters with older coronaviruses or perhaps an unknown one, already been partly prepared for the fight. Understanding exactly how that preparation works, the authors argue, could prove vital not only for explaining the past but for preparing against the next coronavirus threat.