How Long Has COVID-19 Been In Europe?
The ongoing debate over the origin of the SARS-CoV-2 virus and corresponding COVID-19 pandemic is replete with unusual twists and turns. Among the latest is a reexamination of early retrospective blood sample studies suggesting that the virus was present in Europe far earlier than first reported.
In a tweet from March 13 of this year, Stanford University medical professor Dr. Jay Bhattacharya highlighted a tweet from 2021 pointing to two studies showing SARS-CoV-2 antibodies in stored blood samples in France and Italy.
The first thing that must be emphasized is Dr. Bhattacharya's “discovery" is of two relatively old studies from November of 2020 and February of 2021. While the studies are authentic and peer-reviewed, they are not groundbreaking research. Further down in his tweet thread, Dr. Bhattacharya himself asks the question why the studies have remained in obscurity.
Part of the answer may lie in certain problematic aspects of the data.
The Italian Study
The first study was an Italian retrospective study examining 959 blood samples taken from September 2019 to March 2020, as part of a lung cancer screening project.
To test the hypothesis of early circulation of the virus in Italy, we investigated the frequency, timing, and geographic distribution of SARS-CoV-2 exposure in a series of 959 asymptomatic individuals, using proprietary SARS-CoV-2 binding and neutralizing antibodies on the plasma samples repository. The population was enrolled from September 2019 to March 2020 through the SMILE trial (Screening and Multiple Intervention on Lung Epidemics; ClinicalTrials.gov Identifier: NCT03654105), a prospective lung cancer screening study using low-dose computed tomography and blood biomarkers, with the approval of our institutional review board and ethics committee. All eligible participants provided written informed consent.
The first thing to note is that the samples were of asymptomatic patients. By definition, this study targets patients who are demonstrably not sick with COVID-19. While the presence of SARS-CoV-2 antibodies in these patients is intriguing, the lack of symptoms precludes these patients from being realistically considered COVID-19 patients.
Still, the data shows SARS-CoV-2 antibodies in patients in September of 2019, in the Lombardy province of Italy that would be the epicenter of the pandemic in Italy the following spring.
Table 1 reports anti-SARS-CoV-2 RBD antibody detection according to the time of sample collection in Italy. In the first 2 months, September–October 2019, 23/162 (14.2%) patients in September and 27/166 (16.3%) in October displayed IgG or IgM antibodies, or both. The first positive sample (IgM-positive) was recorded on September 3 in the Veneto region, followed by a case in Emilia Romagna (September 4), a case in Liguria (September 5), two cases in Lombardy (Milano Province; September 9), and one in Lazio (Roma; September 11). By the end of September, 13 of the 23 (56.5%) positive samples were recorded in Lombardy, three in Veneto, two in Piedmont, and one each in Emilia Romagna, Liguria, Lazio, Campania, and Friuli. A similar time distribution was observed when considering Lombardy alone (Supplementary Table S2).
However, the data is frustrating because it speaks of finding antibodies, not the virus itself. In fact, this study notes that environmental monitoring (wastewater sampling) does not reveal viral RNA in Lombardy prior to December.
Given the rapid increase in symptomatic cases worldwide, a better understanding of the initial history and epidemiology of COVID-19 could improve the screening strategy and contain the effects of a possible second wave. Evidence from environmental monitoring showed that SARS-CoV-2 was already circulating in northern Italy at the end of 2019.9 Molecular analysis with reverse transcription polymerase chain reaction assays of 40 composite influent wastewater samples collected between October 2019 and February 2020 in three cities and regions in northern Italy (Milan/Lombardy, Turin/Piedmont, and Bologna/Emilia Romagna) showed the presence of viral RNA first occurring in sewage samples collected on December 18 in Milan and Turin. This study also indicates that SARS-CoV-2 was circulating in different geographic regions simultaneously, which agrees with our serologic findings.
While the antibody data is curious, it is far more curious that the antibodies appear to predate the virus in Lombardy by as much as three months. Given that antibody formation is a response to the presence of a virus, it defies what is known about the human immune system for this to happen.
Why has this study not attracted greater attention? Part of the reason may be that its data is muddied. While the authors suggest the study shows a much earlier date for the appearance of the SARS-CoV-2 virus in Europe, the underlying reality is far from certain.
“Something” triggered the antibody response, but was it COVID-19? The data does not let us say that definitely.
The French Study
The second study, published by French researchers in February 2021, cites the Italian study, and concedes the results are far from definitive.
A recent investigation of the presence of SARS-CoV-2 antibodies in 959 adults participating to a trial in Italy with blood samples collected between September 2019 to February 2020 identified 111 (11.6%) samples with a positive receptor-binding protein specific enzyme-linked immunosorbent assay (ELISA), among which 4 samples collected in October, 1 in November and 1 in February were also positive in a qualitative microneutralization assay . This indicates that SARS-CoV-2 could have been present in Italy since the beginning of autumn 2019. However, information on antibody responses at the early stage of the SARS-CoV-2 spread in other European countries or worldwide remains scarce.
The intriguing aspect of the French study is that it did discover at least a few symptomatic patients.
Neutralizing antibodies were detected in 44 (0.48%) participants (23 with a titer of 40, 12 with a titer of 80, 9 with a titer of 160), were undetermined in 15 participants, negative in 498 and not done in 8597 (Fig. 2). Strikingly, 13 participants with positive ELISA-S and SN tests had been sampled between November 5, 2019 and January 30, 2020. Table 1 describes the serological results in these 13 participants, among whom 11 were interviewed. Six of those interviewed did not report any symptom during the weeks preceding the sample collection. Five participants experienced signs of viral respiratory illnesses, and 8 had close contact with persons who exhibited such signs or reported situations at risk of potential SARS-CoV-2 exposure. Of note, participant #7 who was tested positive on Nov 29, 2020 had a second serological sample collected in July 2020 with a positive ELISA-S test and negative SN test—this participant also tested positive in SARS-CoV-2 RT-PCR in September 2020 for new symptoms suggesting a possible reinfection.
13 cases of neutralizing antibodies prior to January 30, 2020, is indeed noteworthy, particularly when 5 of those cases reported signs of viral respiratory illnesses preceding the date of the original blood sample. However, even this study does not identify the presence of virus or viral fragments in the study samples, preventing the study from being categorical evidence of early SARS-CoV-2 circulation in Europe.
If Not COVID-19, Then What?
No infection occurs in a vacuum, and this is especially true for COVID-19. There are 7 known coronaviruses which cause infectious respiratory disease in humans. Additionally, as other early research has indicated, infection by one coronavirus can develop immunity against the other six.
Of the seven coronaviruses associated with disease in humans, SARS-CoV, MERS-CoV and SARS-CoV-2 cause considerable mortality but also share significant sequence homology, and potentially antigenic epitopes capable of inducing an immune response. The degree of similarity is such that perhaps prior exposure to one virus could confer partial immunity to another. Indeed, data suggests a considerable amount of cross-reactivity and recognition by the hosts immune response between different coronavirus infections. While the ongoing COVID-19 outbreak rapidly overwhelmed medical facilities of particularly Europe and North America, accounting for 78% of global deaths, only 8% of deaths have occurred in Asia where the outbreak originated. Interestingly, Asia and the Middle East have previously experienced multiple rounds of coronavirus infections, perhaps suggesting buildup of acquired immunity to the causative SARS-CoV-2 that underlies COVID-19. This article hypothesizes that a causative factor underlying such low morbidity in these regions is perhaps (at least in part) due to acquired immunity from multiple rounds of coronavirus infections and discusses the mechanisms and recent evidence to support such assertions. Further investigations of such phenomenon would allow us to examine strategies to confer protective immunity, perhaps aiding vaccine development.
Accordingly, the question must be asked whether these retrospective studies show early presence of SARS-CoV-2 virus in Europe, or merely coronavirus presence. Even without addressing the potential for false positives among the antibody tests, the lack of symptomatic patients weakens the case for early SARS-CoV-2 circulation in Europe, and renders a claim of early COVID-19 disease spread in Europe wholly unsustainable—with no symptomatic patients there is by definition no disease.
The debate over the origin of the SARS-CoV-2 virus is ongoing, and will likely be ongoing for some time to come. What this latest reminder of the early research on the topic illustrates above all else is the importance of an open mind and a skeptical outlook when reviewing any of the data.
No single study is ever the “final word” on anything. If the pandemic panic hysteria teaches us anything it surely must teach us that.