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Follow-up study in the ski-resort Ischgl: Antibody and T cell responses to SARS-CoV-2 persisted for up to 8 months after infection and transmission of virus was low even during the second infection wave in Austria
Abstract and Figures
Background: In early March 2020, a SARS-CoV-2 outbreak in the ski resort Ischgl in Austria initiated the spread of SARS-CoV-2 throughout Austria and Northern Europe. In a cross-sectional study, we found that the seroprevalence in the adult population of Ischgl had reached 45% by the end of April. To answer the question of how long immunity persists and what effect this high-level immunity had on virus transmission, we performed a follow-up study in early November, 2020.
Methods: Of the 1259 adults that participated in the baseline study, 801 could be included in the follow-up. The study involved the analysis of binding and neutralizing antibodies and T cell responses. In addition, the incidence of SARS-CoV-2 infections in Ischgl was compared to the incidence in similar municipalities in Tyrol throughout 2020.
Findings: For the 801 individuals that participated in both studies, the seroprevalence declined from 51.4% (95% confidence interval (CI) 47.9 - 54.9) to 45.4% (95% CI 42.0 - 49.0). Median antibody concentrations dropped considerably but antibody avidity increased. T cell responses were analysed in 93 cases, including all 4 formerly seropositive cases that had lost antibodies in all assays, three of which still had detectable T cell memory. In addition, the incidence in the second COVID-19 wave that hit Austria in November 2020, was significantly lower in Ischgl than in comparable municipalities in Tyrol or the rest of Austria.
Interpretation: This study has important implications as it shows that although antibodies to SARS-CoV-2 declined, T and B cell memory can be detected for up to 8 months. Complemented by infection prevention measures a level of around 40-45% immunity in Ischgl significantly reduced local virus transmission during the second wave in Austria in November 2020.
Funding: Funding was provided by the government of Tyrol and the FWF Austrian Science Fund.
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... After a maturation process that takes a couple of months, avidity increases and indicates a functionally active antibody pool, as shown for SARS-CoV-1 [13]. Now that recent data on longevity of the immune response to SARS CoV-2 prove persistence of antibodies over a period of 7-8 months [14], characterizing the avidity of SARS-CoV-2 specific antibodies is of key interest. To date only few studies exist which have studied avidity, and only for a much shorter period. ...
... The data from Ischgl 7-8 months after the initial infection [14] could represent a particular basis to understand aspects of the dynamics of the immune response to SARS-CoV-2 M a n u s c r i p t 4 infections due to the above mentioned, especially the high infection rate. Furthermore, the willingness to participate in this study was high. ...
... The main aim of the study was to assess in a large longitudinal study, with one of the longest follow up times currently available, whether the marked increase in avidity of antibodies we observed 7-8 months after an infection [14] was also substantial in old age. Other aims were to assess the dependence on sex and whether a high avidity is correlated with a high neutralization capacity, which would then convey an important role to avidity tests for assessing potential protection against further SARS-CoV-2 infections without necessitating expensive and laborious neutralization assays. ...
The kinetics of IgG avidity maturation during severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection obtained from 217 participants of the Ischgl cohort, Austria, was studied 0.5-1.5 (baseline) and 7-8 months (follow up) after infection. The IgG avidity assay, using a modified IgG ELISA and 5.5 M urea, revealed that old age does not diminish the increase in avidity, detected in all participants positive at both time points, from 18% to 42%. High avidity was associated with a marked residual neutralization capacity in 97.2.% of participants (211/217), which was even higher in the older age group, revealing an important role of avidity assays as easy and cheap surrogate tests for assessing the maturation of the immune system conveying potential protection against further SARS-CoV-2 infections without necessitating expensive and laborious neutralization assays.
La présente note a pour but de faire le point sur l’efficacité de l’immunité post-infectieuse (ou naturelle) acquise par les convalescents du Covid, et sur la pertinence de leur vaccination.
Les dernières recommandations de la Haute Autorité de Santé concluent à l’intérêt de vacciner les convalescents à 6 mois de l’infection. Elles se basent essentiellement sur des études biologiques, qui ne sont pas nécessairement corrélées à la protection effectivement acquise sur le terrain. Elles n’évaluent pas non plus de balance des risques propre à la vaccination des convalescents.
Notre recension critique des études épidémiologiques réalisées jusqu’ici montre que l’immunité naturelle s’avère particulièrement efficace (aussi bien contre le risque d’infection que contre le risque de forme symptomatique ou sévère), durable (à plus d’un an), et robuste (face au variant Delta).
L’efficacité de l’immunité naturelle, au moins comparable à celle de l’immunité artificielle post-vaccinale à court terme (4 mois), se montre supérieure à moyen et long terme.
La plupart des protocoles ont en outre tendance à sous-estimer l’efficacité de l’immunité post-infectieuse et à surestimer celle de l’immunité post-vaccinale.
Les données cliniques actuelles ne permettent pas de déterminer une balance des risques qui soit assurément favorable à la vaccination des convalescents.
Dans le cadre d’une vaccination qui demeure expérimentale, la rigueur la plus élémentaire, aussi bien scientifique que clinique et morale, voudrait donc que l’on s’abstienne de vacciner plus avant les convalescents du Covid — et que l’on s’abstienne de supprimer les témoins.
Background
In early March 2020, a SARS-CoV-2 outbreak in the ski resort Ischgl in Austria initiated the spread of SARS-CoV-2 throughout Austria and Northern Europe.
Methods
Between April 21st and 27th 2020, a cross-sectional epidemiologic study targeting the full population of Ischgl (n = 1867), of which 79% could be included (n = 1473, incl. 214 children), was performed. For each individual, the study involved a SARS-CoV-2 PCR, antibody testing and structured questionnaires. A mathematical model was used to help understand the influence of the determined seroprevalence on virus transmission.
Results
The seroprevalence was 42.4% (95% confidence interval (CI) 39.8–44.7). Individuals under 18 showed a significantly lower seroprevalence of 27.1% (95% CI 21.3-33.6) than adults (45%; 95% CI 42.2–47.7; OR of 0.455, 95% CI 0.356–0.682, p < 0.001). Of the seropositive individuals, 83.7% had not been diagnosed to have had SARS-CoV-2 infection previously. The clinical course was generally mild. Over the previous two months, two COVID-19-related deaths had been recorded, corresponding to an infection fatality rate of 0.25% (95% CI 0.03–0.91). Only 8 (0.5 %) individuals were newly diagnosed to be infected with SARS-CoV-2 during this study.
Conclusions
Ischgl was hit early and hard by SARS-CoV-2 leading to a high local seroprevalence of 42.4%, which was lower in individuals below the age of 18 than in adults. Mathematical modeling suggests that a drastic decline of newly infected individuals in Ischgl by the end of April occurred due to the dual impact from the non-pharmacological interventions and a high immunization of the Ischgl population.
Background
A key question concerning coronavirus disease 2019 (COVID‐19) is how effective and long lasting immunity against this disease is in individuals who were previously infected with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). We aimed to evaluate the risk of SARS‐CoV‐2 re‐infections in the general population in Austria.
Methods
This is a retrospective observational study using national SARS‐CoV‐2 infection data from the Austrian epidemiological reporting system. As the primary outcome, we aim to compare the odds of SARS‐CoV‐2 re‐infections of COVID‐19 survivors of the first wave (February to April 30, 2020) versus the odds of first infections in the remainder general population by tracking polymerase chain reaction (PCR)‐confirmed infections of both groups during the second wave from September 1 to November 30, 2020. Re‐infection counts are tentative, since it cannot be excluded that the positive PCR in the first and/or second wave might have been a false positive.
Results
We recorded 40 tentative re‐infections in 14,840 COVID‐19 survivors of the first wave (0.27%) and 253,581 infections in 8,885,640 individuals of the remaining general population (2.85%) translating into an odds ratio (95% confidence interval) of 0.09 (0.07 to 0.13).
Conclusions
We observed a relatively low re‐infection rate of SARS‐CoV‐2 in Austria. Protection against SARS‐CoV‐2 after natural infection is comparable to the highest available estimates on vaccine efficacies. Further well‐designed research on this issue is urgently needed for improving evidence‐based decisions on public health measures and vaccination strategies.
There are only few data concerning persistence of neutralizing antibodies (NAbs) among SARS-CoV-2-infected healthcare workers (HCW). These individuals are particularly exposed to SARS-CoV-2 infection and at potential risk of reinfection. We followed 26 HCW with mild COVID-19 three weeks (D21), two months (M2) and three months (M3) after the onset of symptoms. All the HCW had anti-receptor binding domain (RBD) IgA at D21, decreasing to 38.5% at M3 ( p < 0.0001). Concomitantly a significant decrease in NAb titers was observed between D21 and M2 ( p = 0.03) and between D21 and M3 ( p < 0.0001). Here, we report that SARS-CoV-2 can elicit a NAb response correlated with anti-RBD antibody levels. However, this neutralizing activity declines, and may even be lost, in association with a decrease in systemic IgA antibody levels, from two months after disease onset. This short-lasting humoral protection supports strong recommendations to maintain infection prevention and control measures in HCW, and suggests that periodic boosts of SARS-CoV-2 vaccination may be required.
Variable memory
Immune memory against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) helps to determine protection against reinfection, disease risk, and vaccine efficacy. Using 188 human cases across the range of severity of COVID-19, Dan et al. analyzed cross-sectional data describing the dynamics of SARS-CoV-2 memory B cells, CD8 ⁺ T cells, and CD4 ⁺ T cells for more than 6 months after infection. The authors found a high degree of heterogeneity in the magnitude of adaptive immune responses that persisted into the immune memory phase to the virus. However, immune memory in three immunological compartments remained measurable in greater than 90% of subjects for more than 5 months after infection. Despite the heterogeneity of immune responses, these results show that durable immunity against secondary COVID-19 disease is a possibility for most individuals.
Science , this issue p. eabf4063
Neutralizing antibodies are a major correlate of protection for many viruses including the novel coronavirus SARS-CoV-2. Thus, vaccine candidates should potently induce neutralizing antibodies to render effective protection from infection. A variety of in vitro assays for the detection of SARS-CoV-2 neutralizing antibodies has been described. However, validation of the different assays against each other is important to allow comparison of different studies. Here, we compared four different SARS-CoV-2 neutralization assays using the same set of patient samples. Two assays used replication competent SARS-CoV-2, a focus forming assay and a TCID50-based assay, while the other two assays used replication defective lentiviral or vesicular stomatitis virus (VSV)-based particles pseudotyped with SARS-CoV-2 spike. All assays were robust and produced highly reproducible neutralization titers. Titers of neutralizing antibodies correlated well between the different assays and with the titers of SARS-CoV-2 S-protein binding antibodies detected in an ELISA. Our study showed that commonly used SARS-CoV-2 neutralization assays are robust and that results obtained with different assays are comparable.
Understanding the nature of immunity following mild/asymptomatic infection with SARS-CoV-2 is crucial to controlling the pandemic. We analyzed T cell and neutralizing antibody responses in 136 healthcare workers (HCW) 16-18 weeks after United Kingdom lockdown, 76 of whom had mild/asymptomatic SARS-CoV-2 infection captured by serial sampling. Neutralizing antibodies (nAb) were present in 89% of previously infected HCW. T cell responses tended to be lower following asymptomatic infection than in those reporting case-definition symptoms of COVID-19, while nAb titers were maintained irrespective of symptoms. T cell and antibody responses were sometimes discordant. Eleven percent lacked nAb and had undetectable T cell responses to spike protein but had T cells reactive with other SARS-CoV-2 antigens. Our findings suggest that the majority of individuals with mild or asymptomatic SARS-CoV-2 infection carry nAb complemented by multispecific T cell responses at 16-18 weeks after mild or asymptomatic SARS-CoV-2 infection.
Superspreading events shaped the coronavirus disease 2019 (COVID-19) pandemic, and their rapid identification and containment are essential for disease control. Here, we provide a national-scale analysis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) superspreading during the first wave of infections in Austria, a country that played a major role in initial virus transmissions in Europe. Capitalizing on Austria’s well-developed epidemiological surveillance system, we identified major SARS-CoV-2 clusters during the first wave of infections and performed deep whole-genome sequencing of more than 500 virus samples. Phylogenetic-epidemiological analysis enabled the reconstruction of superspreading events and charts a map of tourism-related viral spread originating from Austria in spring 2020. Moreover, we exploited epidemiologically well-defined clusters to quantify SARS-CoV-2 mutational dynamics, including the observation of low-frequency mutations that progressed to fixation within the infection chain. Time-resolved virus sequencing unveiled viral mutation dynamics within individuals with COVID-19, and epidemiologically validated infector-infectee pairs enabled us to determine an average transmission bottleneck size of 10 ³ SARS-CoV-2 particles. In conclusion, this study illustrates the power of combining epidemiological analysis with deep viral genome sequencing to unravel the spread of SARS-CoV-2 and to gain fundamental insights into mutational dynamics and transmission properties.
Background:
The first cases of COVID-19 caused by the SARS-CoV-2 virus were reported in China in December 2019. The disease has since spread globally. Many countries have instated measures to slow the spread of the virus. Information about the spread of the virus in a country can inform the gradual reopening of a country and help to avoid a second wave of infections. Our study focuses on Denmark, which is opening up when this study is performed (end-May 2020) after a lockdown in mid-March.
Methods:
We perform a phylogenetic analysis of 742 publicly available Danish SARS-CoV-2 genome sequences and put them into context using sequences from other countries.
Results:
Our findings are consistent with several introductions of the virus to Denmark from independent sources. We identify several chains of mutations that occurred in Denmark. In at least one case we find evidence that the virus spread from Denmark to other countries. A number of the mutations found in Denmark are non-synonymous, and in general there is a considerable variety of strains. The proportions of the most common haplotypes remain stable after lockdown.
Conclusion:
Employing phylogenetic methods on Danish genome sequences of SARS-CoV-2, we exemplify how genetic data can be used to trace the introduction of a virus to a country. This provides alternative means for verifying existing assumptions. For example, our analysis supports the hypothesis that the virus was brought to Denmark by skiers returning from Ischgl. On the other hand, we identify transmission routes which suggest that Denmark was part of a network of countries among which the virus was being transmitted. This challenges the common narrative that Denmark only got infected from abroad. Our analysis concerning the ratio of haplotypes does not indicate that the major haplotypes appearing in Denmark have a different degree of virality.
Infection with SARS-CoV-2 has become pandemic and the duration of protective immunity to the virus is unknown. Cases of persons reinfected with the virus are being reported with increasing frequency. At present it is unclear how common reinfection with SARS-CoV-2 is and how long serum antibodies and virus-specific T cells persist after infection. For many other respiratory virus infections, including influenza and the seasonal coronaviruses that cause colds, serum antibodies persist for only months to a few years and reinfections are very common. Here we review what is known about the duration of immunity and reinfection with coronaviruses, including SARS-CoV-2, and well as the duration of immunity to other viruses and virus vaccines. These findings have implications for the need of continued protective measures and for vaccines for persons previously infected with SARS-CoV-2.
Background
The degree of protective immunity conferred by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently unknown. As such, the possibility of reinfection with SARS-CoV-2 is not well understood. We describe an investigation of two instances of SARS-CoV-2 infection in the same individual.
Methods
A 25-year-old man who was a resident of Washoe County in the US state of Nevada presented to health authorities on two occasions with symptoms of viral infection, once at a community testing event in April, 2020, and a second time to primary care then hospital at the end of May and beginning of June, 2020. Nasopharyngeal swabs were obtained from the patient at each presentation and twice during follow-up. Nucleic acid amplification testing was done to confirm SARS-CoV-2 infection. We did next-generation sequencing of SARS-CoV-2 extracted from nasopharyngeal swabs. Sequence data were assessed by two different bioinformatic methodologies. A short tandem repeat marker was used for fragment analysis to confirm that samples from both infections came from the same individual.
Findings
The patient had two positive tests for SARS-CoV-2, the first on April 18, 2020, and the second on June 5, 2020, separated by two negative tests done during follow-up in May, 2020. Genomic analysis of SARS-CoV-2 showed genetically significant differences between each variant associated with each instance of infection. The second infection was symptomatically more severe than the first.
Interpretation
Genetic discordance of the two SARS-CoV-2 specimens was greater than could be accounted for by short-term in vivo evolution. These findings suggest that the patient was infected by SARS-CoV-2 on two separate occasions by a genetically distinct virus. Thus, previous exposure to SARS-CoV-2 might not guarantee total immunity in all cases. All individuals, whether previously diagnosed with COVID-19 or not, should take identical precautions to avoid infection with SARS-CoV-2. The implications of reinfections could be relevant for vaccine development and application.
Funding
Nevada IDEA Network of Biomedical Research, and the National Institute of General Medical Sciences (National Institutes of Health).