Maternal transfer of IgA and IgG SARS-CoV-2 specific antibodies transplacentally and via breast milk feeding.

BACKGROUND: Although there have been many studies on antibody responses to SARS-CoV-2 in breast milk, very few have looked at the fate of these in the infant, and whether they are delivered to immunologically relevant sites in infants. METHODS: Mother/infant pairs (mothers who breast milk fed and who were SARS-CoV-2 vaccinated before or after delivery) were recruited for this cross-sectional study. Mother blood, mother breast milk, infant blood, infant nasal specimen, and infant stool was tested for IgA and IgG antibodies against SARS-CoV-2 spike trimer. RESULTS: Thirty-one mother/infant pairs were recruited. Breast milk fed infants acquired systemic anti-spike IgG antibodies only if their mothers were vaccinated antepartum (100% Antepartum; 0% Postpartum; P<0.0001). Breast milk fed infants acquired mucosal anti-spike IgG antibodies (in the nose) only if their mothers were vaccinated antepartum (89% Antepartum; 0% Postpartum; P<0.0001). None of the infants in either group had anti-spike IgA in the blood. Surprisingly, 33% of the infants whose mothers were vaccinated antepartum had high titer anti-spike IgA in the nose (33% Antepartum; 0% Postpartum; P = 0.03). Half-life of maternally transferred plasma IgG antibodies in the Antepartum infant cohort was ~70 days. CONCLUSION: Vaccination antepartum followed by breast milk feeding appears to be the best way to provide systemic and local anti-SARS-CoV-2 antibodies for infants. The presence of high titer SARS-CoV-2-specific IgA in the nose of infants points to the potential importance of breast milk feeding early in life for maternal transfer of mucosal IgA antibodies. Expectant mothers should consider becoming vaccinated antepartum and consider breast milk feeding for optimal transfer of systemic and mucosal antibodies to their infants.

Mucosal and Systemic Responses to Severe Acute Respiratory Syndrome Coronavirus 2 Vaccination Determined by Severity of Primary Infection.

With much of the world infected with or vaccinated against severe acute respiratory syndrome coronavirus 2 (commonly abbreviated SARS-CoV-2; abbreviated here SARS2), understanding the immune responses to the SARS2 spike (S) protein in different situations is crucial to controlling the pandemic. We studied the clinical, systemic, mucosal, and cellular responses to two doses of SARS2 mRNA vaccines in 62 individuals with and without prior SARS2 infection that were divided into three groups based on antibody serostatus prior to vaccination and/or degree of disease symptoms among those with prior SARS2 infection: antibody negative (naive), low symptomatic, and symptomatic. Antibody negative were subjects who were antibody negative (i.e., those with no prior infection). Low symptomatic subjects were those who were antibody negative and had minimal or no symptoms at time of SARS2 infection. Symptomatic subjects were those who were antibody positive and symptomatic at time of SARS2 infection. All three groups were then studied when they received their SARS2 mRNA vaccines. In the previously SARS2-infected (based on antibody test) low symptomatic and symptomatic groups, reactogenic symptoms related to a recall response were elicited after the first vaccination. Anti-S trimer IgA and IgG titers, and neutralizing antibody titers, peaked after the 1st vaccination in the previously SARS2-infected groups and were significantly higher than for the SARS2 antibody-negative group in the plasma and nasal samples at most time points. Nasal and plasma IgA antibody responses were significantly higher in the low symptomatic group than in the symptomatic group at most time points. After the first vaccination, differences in cellular immunity were not evident between groups, but the activation-induced cell marker (AIM+) CD4+ cell response correlated with durability of IgG humoral immunity against the SARS2 S protein. In those SARS2-infected subjects, severity of infection dictated plasma and nasal IgA responses in primary infection as well as response to vaccination (peak responses and durability), which could have implications for continued protection against reinfection. Lingering differences between the SARS2-infected and SARS2-naive up to 10 months postvaccination could explain the decreased reinfection rates in the SARS2-infected vaccinees recently reported and suggests that additional strategies (such as boosting of the SARS2-naive vaccinees) are needed to narrow the differences observed between these groups. IMPORTANCE This study on SARS2 vaccination in those with and without previous exposure to the virus demonstrates that severity of infection dictates IgA responses in primary infection as well as response to vaccination (peak responses and durability), which could have implications for continued protection against reinfection.

Determining the SARS-CoV-2 serological immunoassay test performance indices based on the test results frequency distribution.

Introduction: Coronavirus disease 2019 (COVID-19) is known to induce robust antibody response in most of the affected individuals. The objective of the study was to determine if we can harvest the test sensitivity and specificity of a commercial serologic immunoassay merely based on the frequency distribution of the SARS-CoV-2 immunoglobulin (Ig) G concentrations measured in a population-based seroprevalence study. Materials and methods: The current study was conducted on a subset of a previously published dataset from the canton of Geneva. Data were taken from two non-consecutive weeks (774 samples from May 4-9, and 658 from June 1-6, 2020). Assuming that the frequency distribution of the measured SARS-CoV-2 IgG is binormal (an educated guess), using a non-linear regression, we decomposed the distribution into its two Gaussian components. Based on the obtained regression coefficients, we calculated the prevalence of SARS-CoV-2 infection, the sensitivity and specificity, and the most appropriate cut-off value for the test. The obtained results were compared with those obtained from a validity study and a seroprevalence population-based study. Results: The model could predict more than 90% of the variance observed in the SARS-CoV-2 IgG distribution. The results derived from our model were in good agreement with the results obtained from the seroprevalence and validity studies. Altogether 138 of 1432 people had SARS-CoV-2 IgG ≥ 0.90, the cut-off value which maximized the Youden's index. This translates into a true prevalence of 7.0% (95% confidence interval 5.4% to 8.6%), which is in keeping with the estimated prevalence of 7.7% derived from our model. Our model can provide the true prevalence. Conclusions: Having an educated guess about the distribution of test results, the test performance indices can be derived with acceptable accuracy merely based on the test results frequency distribution without the need for conducting a validity study and comparing the test results against a gold-standard test.

Use of oral polio vaccine and the incidence of COVID-19 in the world.

BACKGROUND: Several live attenuated vaccines were shown to provide temporary protection against a variety of infectious diseases through stimulation of the host innate immune system. OBJECTIVE: To test the hypothesis that countries using oral polio vaccine (OPV) have a lower cumulative number of cases diagnosed with COVID-19 per 100,000 population (CP100K) compared with those using only inactivated polio vaccine (IPV). METHODS: In an ecological study, the CP100K was compared between countries using OPV vs IPV. We used a random-effect meta-analysis technique to estimate the pooled mean for CP100K. We also used negative binomial regression with CP100K as the dependent variable and the human development index (HDI) and the type of vaccine used as independent variables. RESULTS: The pooled estimated mean CP100K was 4970 (95% CI 4030 to 5900) cases per 100,000 population for countries using IPV, significantly (p<0.001) higher than that for countries using OPV-1580 (1190 to 1960). Countries with higher HDI prefer to use IPV; those with lower HDI commonly use OPV. Both HDI and the type of vaccine were independent predictors of CP100K. Use of OPV compared to IPV could independently decrease the CP100K by an average of 30% at the mean HDI of 0.72. CONCLUSIONS: Countries using OPV have a lower incidence of COVID-19 compared to those using IPV. This might suggest that OPV may either prevent SARS-CoV-2 infection at individual level or slow down the transmission at the community level.

COVID-19 Infection Among Women in Iran Exposed vs Unexposed to Children Who Received Attenuated Poliovirus Used in Oral Polio Vaccine.

Importance: Live attenuated vaccines may provide short-term protection against infectious diseases through stimulation of the innate immune system. Objective: To evaluate whether passive exposure to live attenuated poliovirus is associated with diminished symptomatic infection with SARS-CoV-2. Design, Setting, and Participants: In a longitudinal cohort study involving 87 923 people conducted between March 20 and December 20, 2020, the incidence of COVID-19 was compared between 2 groups of aged-matched women with and without exposure to live attenuated poliovirus in the oral polio vaccine (OPV). Participants were people receiving health care services from the Petroleum Industry Health Organization and residing in 2 cities in Iran (ie, Ahwaz and Shiraz). Participants were women aged 18 to 48 years whose children were aged 18 months or younger and a group of age-matched women from the same residence who had had no potential exposure to OPV. Exposures: Indirect exposure to live attenuated poliovirus in OPV. Main Outcomes and Measures: Symptomatic COVID-19, diagnosed by reverse transcription-polymerase chain reaction. Results: After applying the inclusion and exclusion criteria, 419 mothers (mean [SD] age, 35.5 [4.9] years) indirectly exposed to the OPV and 3771 age-matched women (mean [SD] age, 35.7 [5.3] years) who had no exposure to OPV were available for analysis. COVID-19 was diagnosed in 1319 of the 87 923 individuals in the study population (151 per 10 000 population) during the study period. None of the mothers whose children received OPV developed COVID-19 after a median follow-up of 141 days (IQR, 92-188 days; range, 1-270 days); 28 women (0.74%; 95% CI, 0.47%-1.02%) in the unexposed group were diagnosed with COVID-19 during the 9 months of the study. Point-by-point comparison of the survival curves of the exposed and unexposed groups found that indirect exposure to OPV was significantly associated with decreased COVID-19 acquisition; probability of remaining without infection was 1.000 (95% CI, 1.000-1.000) in the exposed group vs 0.993 (95% CI, 0.990-0.995) in the unexposed group after 9 months (P < .001). Conclusions and Relevance: In this cohort study, indirect exposure to live attenuated poliovirus was associated with decreased symptomatic infection with COVID-19. Further study of the potential protective effect of OPV should be conducted, especially in nations where OPV is already in use for polio prevention and specific COVID-19 vaccines are delayed, less affordable, or fail to meet demand.

Temperature, Humidity and Latitude Analysis to Predict Potential Spread and Seasonality for COVID-19

BACKGROUND: A significant number of infectious diseases display seasonal patterns in their incidence, including human coronaviruses. Betacoronaviruses such as MERS-CoV and SARS-CoV are not thought to be seasonal. METHODS: We examined climate data from cities with significant community spread of COVID-19 using ERA-5 reanalysis, and compared to areas that are either not affected, or do not have significant community spread. FINDINGS: To date, Coronavirus Disease 2019 (COVID-19), caused by SARS-CoV-2, has established significant community spread in cities and regions along a narrow east west distribution roughly along the 30-50o N' corridor at consistently similar weather patterns consisting of average temperatures of 5-11oC, combined with low specific (3-6 g/kg) and absolute humidity (4-7 g/m3). There has been a lack of significant community establishment in expected locations that are based only on population proximity and extensive population interaction through travel. INTERPRETATION: The distribution of significant community outbreaks along restricted latitude, temperature, and humidity are consistent with the behavior of a seasonal respiratory virus. Additionally, we have proposed a simplified model that shows a zone at increased risk for COVID-19 spread. Using weather modeling, it may be possible to predict the regions most likely to be at higher risk of significant community spread of COVID-19 in the upcoming weeks, allowing for concentration of public health efforts on surveillance and containment.

Role of miR-2392 in driving SARS-CoV-2 infection.

MicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene regulation that have a major impact on many diseases and provide an exciting avenue toward antiviral therapeutics. From patient transcriptomic data, we determined that a circulating miRNA, miR-2392, is directly involved with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) machinery during host infection. Specifically, we show that miR-2392 is key in driving downstream suppression of mitochondrial gene expression, increasing inflammation, glycolysis, and hypoxia, as well as promoting many symptoms associated with coronavirus disease 2019 (COVID-19) infection. We demonstrate that miR-2392 is present in the blood and urine of patients positive for COVID-19 but is not present in patients negative for COVID-19. These findings indicate the potential for developing a minimally invasive COVID-19 detection method. Lastly, using in vitro human and in vivo hamster models, we design a miRNA-based antiviral therapeutic that targets miR-2392, significantly reduces SARS-CoV-2 viability in hamsters, and may potentially inhibit a COVID-19 disease state in humans.

Performance of nucleocapsid and spike-based SARS-CoV-2 serologic assays.

There is an urgent need for an accurate antibody test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We have developed 3 ELISA methods, trimer spike IgA, trimer spike IgG, and nucleocapsid IgG, for detecting anti-SARS-CoV-2 antibodies. We evaluated their performance along with four commercial ELISAs, EDI™ Novel Coronavirus COVID-19 ELISA IgG and IgM, Euroimmun Anti-SARS-CoV-2 ELISA IgG and IgA, and one lateral flow assay, DPP® COVID-19 IgM/IgG System (Chembio). Both sensitivity and specificity were evaluated and the probable causes of false-positive reactions were determined. The assays were evaluated using 300 pre-epidemic samples and 100 PCR-confirmed COVID-19 samples. The sensitivities and specificities of the assays were as follows: 90%/100% (in-house trimer spike IgA), 90%/99.3% (in-house trimer spike IgG), 89%/98.3% (in-house nucleocapsid IgG), 73.7%/100% (EDI nucleocapsid IgM), 84.5%/95.1% (EDI nucleocapsid IgG), 95%/93.7% (Euroimmun S1 IgA), 82.8%/99.7% (Euroimmun S1 IgG), 82.0%/91.7% (Chembio nucleocapsid IgM), 92%/93.3% (Chembio nucleocapsid IgG). The presumed causes of false positive results from pre-epidemic samples in commercial and in-house assays were mixed. In some cases, assays lacked reproducibility. In other cases, reactivity was abrogated by competitive inhibition (spiking the sample with the same antigen that was used for coating ELISAs prior to performing the assay), suggesting positive reaction could be attributed to the presence of antibodies against these antigens. In other cases, reactivity was consistently detected but not abrogated by the spiking, suggesting positive reaction was not attributed to the presence of antibodies against these antigens. Overall, there was wide variability in assay performance using our samples, with in-house tests exhibiting the highest combined sensitivity and specificity. The causes of "false positivity" in pre-epidemic samples may be due to plasma antibodies apparently reacting with the corresponding antigen, or spurious reactivity may be directed against non-specific components in the assay system. Identification of these targets will be essential to improving assay performance.

Specificity and Performance of Nucleocapsid and Spike-based SARS-CoV-2 Serologic Assays.

There is an urgent need for an accurate antibody test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this paper, we have developed 3 ELISA methods, trimer spike IgA, trimer spike IgG, and nucleocapsid IgG, for detecting anti-SARS-CoV-2 antibodies. We evaluated their performance in comparison with four commercial ELISAs, EDI Novel Coronavirus COVID-19 ELISA IgG and IgM, Euroimmun Anti-SARS-CoV-2 ELISA IgG and IgA, and one lateral flow assay, DPP COVID-19 IgM/IgG System (Chembio). Both sensitivity and specificity were evaluated and the causes of false-positive reactions were determined. The assays were compared using 300 pre-epidemic samples and 100 PCR-confirmed COVID-19 samples. The sensitivities and specificities of the assays were as follows: 90%/100% (in-house trimer spike IgA), 90%/99.3% (in-house trimer spike IgG), 89%/98.3% (in-house nucleocapsid IgG), 73.7%/100% (EDI nucleocapsid IgM), 84.5%/95.1% (EDI nucleocapsid IgG), 95%/93.7% (Euroimmun S1 IgA), 82.8%/99.7% (Euroimmun S1 IgG), 82.0%/91.7% (Chembio nucleocapsid IgM), 92%/93.3% (Chembio nucleocapsid IgG). The presumed causes of positive signals from pre-epidemic samples in commercial and in-house assays were mixed. In some cases, positivity varied with assay repetition. In other cases, reactivity was abrogated by competitive inhibition (spiking the sample with analyte prior to performing the assay). In other cases, reactivity was consistently detected but not abrogated by analyte spiking. Overall, there was wide variability in assay performance using our samples, with in-house tests exhibiting the highest combined sensitivity and specificity. The causes of false positivity in pre-epidemic samples may be due to plasma antibodies apparently reacting with the analyte, or spurious reactivity may be directed against non-specific components in the assay system. Identification of these targets will be essential to improving assay performance.

Temperature, Humidity and Latitude Analysis to Predict Potential Spread and Seasonality for COVID-19.

BACKGROUND: A significant number of infectious diseases display seasonal patterns in their incidence, including human coronaviruses. Betacoronaviruses such as MERS-CoV and SARS-CoV are not thought to be seasonal. METHODS: We examined climate data from cities with significant community spread of COVID-19 using ERA-5 reanalysis, and compared to areas that are either not affected, or do not have significant community spread. FINDINGS: To date, Coronavirus Disease 2019 (COVID-19), caused by SARS-CoV-2, has established significant community spread in cities and regions along a narrow east west distribution roughly along the 30-50o N' corridor at consistently similar weather patterns consisting of average temperatures of 5-11oC, combined with low specific (3-6 g/kg) and absolute humidity (4-7 g/m3). There has been a lack of significant community establishment in expected locations that are based only on population proximity and extensive population interaction through travel. INTERPRETATION: The distribution of significant community outbreaks along restricted latitude, temperature, and humidity are consistent with the behavior of a seasonal respiratory virus. Additionally, we have proposed a simplified model that shows a zone at increased risk for COVID-19 spread. Using weather modeling, it may be possible to predict the regions most likely to be at higher risk of significant community spread of COVID-19 in the upcoming weeks, allowing for concentration of public health efforts on surveillance and containment.

Temperature, Humidity, and Latitude Analysis to Estimate Potential Spread and Seasonality of Coronavirus Disease 2019 (COVID-19).

Importance: Coronavirus disease 2019 (COVID-19) infection has resulted in a global crisis. Investigating the potential association of climate and seasonality with the spread of this infection could aid in preventive and surveillance strategies. Objective: To examine the association of climate with the spread of COVID-19 infection. Design, Setting, and Participants: This cohort study examined climate data from 50 cities worldwide with and without substantial community spread of COVID-19. Eight cities with substantial spread of COVID-19 (Wuhan, China; Tokyo, Japan; Daegu, South Korea; Qom, Iran; Milan, Italy; Paris, France; Seattle, US; and Madrid, Spain) were compared with 42 cities that have not been affected or did not have substantial community spread. Data were collected from January to March 10, 2020. Main Outcomes and Measures: Substantial community transmission was defined as at least 10 reported deaths in a country as of March 10, 2020. Climate data (latitude, mean 2-m temperature, mean specific humidity, and mean relative humidity) were obtained from ERA-5 reanalysis. Results: The 8 cities with substantial community spread as of March 10, 2020, were located on a narrow band, roughly on the 30° N to 50° N corridor. They had consistently similar weather patterns, consisting of mean temperatures of between 5 and 11 °C, combined with low specific humidity (3-6 g/kg) and low absolute humidity (4-7 g/m3). There was a lack of substantial community establishment in expected locations based on proximity. For example, while Wuhan, China (30.8° N) had 3136 deaths and 80 757 cases, Moscow, Russia (56.0° N), had 0 deaths and 10 cases and Hanoi, Vietnam (21.2° N), had 0 deaths and 31 cases. Conclusions and Relevance: In this study, the distribution of substantial community outbreaks of COVID-19 along restricted latitude, temperature, and humidity measurements was consistent with the behavior of a seasonal respiratory virus. Using weather modeling, it may be possible to estimate the regions most likely to be at a higher risk of substantial community spread of COVID-19 in the upcoming weeks, allowing for concentration of public health efforts on surveillance and containment.