Immunology of COVID-19: Current State of the Science.

Summary Background Viral load kinetics and duration of viral shedding are important determinants for disease transmission. We aimed to characterise viral load dynamics, duration of viral RNA shedding, and viable virus shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in various body fluids, and to compare SARS-CoV-2, SARS-CoV, and Middle East respiratory syndrome coronavirus (MERS-CoV) viral dynamics. Methods In this systematic review and meta-analysis, we searched databases, including MEDLINE, Embase, Europe PubMed Central, medRxiv, and bioRxiv, and the grey literature, for research articles published between Jan 1, 2003, and June 6, 2020. We included case series (with five or more participants), cohort studies, and randomised controlled trials that reported SARS-CoV-2, SARS-CoV, or MERS-CoV infection, and reported viral load kinetics, duration of viral shedding, or viable virus. Two authors independently extracted data from published studies, or contacted authors to request data, and assessed study quality and risk of bias using the Joanna Briggs Institute Critical Appraisal Checklist tools. We calculated the mean duration of viral shedding and 95% CIs for every study included and applied the random-effects model to estimate a pooled effect size. We used a weighted meta-regression with an unrestricted maximum likelihood model to assess the effect of potential moderators on the pooled effect size. This study is registered with PROSPERO, CRD42020181914. Findings 79 studies (5340 individuals) on SARS-CoV-2, eight studies (1858 individuals) on SARS-CoV, and 11 studies (799 individuals) on MERS-CoV were included. Mean duration of SARS-CoV-2 RNA shedding was 17·0 days (95% CI 15·5–18·6; 43 studies, 3229 individuals) in upper respiratory tract, 14·6 days (9·3–20·0; seven studies, 260 individuals) in lower respiratory tract, 17·2 days (14·4–20·1; 13 studies, 586 individuals) in stool, and 16·6 days (3·6–29·7; two studies, 108 individuals) in serum samples. Maximum shedding duration was 83 days in the upper respiratory tract, 59 days in the lower respiratory tract, 126 days in stools, and 60 days in serum. Pooled mean SARS-CoV-2 shedding duration was positively associated with age (slope 0·304 [95% CI 0·115–0·493]; p=0·0016). No study detected live virus beyond day 9 of illness, despite persistently high viral loads, which were inferred from cycle threshold values. SARS-CoV-2 viral load in the upper respiratory tract appeared to peak in the first week of illness, whereas that of SARS-CoV peaked at days 10–14 and that of MERS-CoV peaked at days 7–10. Interpretation Although SARS-CoV-2 RNA shedding in respiratory and stool samples can be prolonged, duration of viable virus is relatively short-lived. SARS-CoV-2 titres in the upper respiratory tract peak in the first week of illness. Early case finding and isolation, and public education on the spectrum of illness and period of infectiousness are key to the effective containment of SARS-CoV-2. Funding None.

SARS-CoV-2, SARS-CoV, and MERS-CoV viral load dynamics, duration of viral shedding, and infectiousness: a systematic review and meta-analysis

Estimating the size of the coronavirus disease 2019 (COVID-19) pandemic and the infection severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is made challenging by inconsistencies in the available data. The number of deaths associated with COVID-19 is often used as a key indicator for the size of the epidemic, but the observed number of deaths represents only a minority of all infections1,2. In addition, the heterogeneous burdens in nursing homes and the variable reporting of deaths of older individuals can hinder direct comparisons of mortality rates and the underlying levels of transmission across countries3. Here we use age-specific COVID-19-associated death data from 45 countries and the results of 22 seroprevalence studies to investigate the consistency of infection and fatality patterns across multiple countries. We find that the age distribution of deaths in younger age groups (less than 65 years of age) is very consistent across different settings and demonstrate how these data can provide robust estimates of the share of the population that has been infected. We estimate that the infection fatality ratio is lowest among 5-9-year-old children, with a log-linear increase by age among individuals older than 30 years. Population age structures and heterogeneous burdens in nursing homes explain some but not all of the heterogeneity between countries in infection fatality ratios. Among the 45 countries included in our analysis, we estimate that approximately 5% of these populations had been infected by 1 September 2020, and that much higher transmission rates have probably occurred in a number of Latin American countries. This simple modelling framework can help countries to assess the progression of the pandemic and can be applied in any scenario for which reliable age-specific death data are available.

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Age-specific mortality and immunity patterns of SARS-CoV-2.

Objective To determine the diagnostic accuracy of
 serological tests for coronavirus disease-2019
 (covid-19). Design Systematic review and meta-analysis. Data sources Medline, bioRxiv, and medRxiv from 1 January to
 30 April 2020, using subject headings or
 subheadings combined with text words for the
 concepts of covid-19 and serological tests for
 covid-19. Eligibility criteria and data
 analysis Eligible studies measured sensitivity or
 specificity, or both of a covid-19 serological
 test compared with a reference standard of viral
 culture or reverse transcriptase polymerase chain
 reaction. Studies were excluded with fewer than
 five participants or samples. Risk of bias was
 assessed using quality assessment of diagnostic
 accuracy studies 2 (QUADAS-2). Pooled sensitivity
 and specificity were estimated using random
 effects bivariate meta-analyses. Main outcome measures The primary outcome was overall sensitivity and
 specificity, stratified by method of serological
 testing (enzyme linked immunosorbent assays
 (ELISAs), lateral flow immunoassays (LFIAs), or
 chemiluminescent immunoassays (CLIAs)) and
 immunoglobulin class (IgG, IgM, or both).
 Secondary outcomes were stratum specific
 sensitivity and specificity within subgroups
 defined by study or participant characteristics,
 including time since symptom onset. Results 5016 references were identified and 40 studies
 included. 49 risk of bias assessments were carried
 out (one for each population and method
 evaluated). High risk of patient selection bias
 was found in 98% (48/49) of assessments and high
 or unclear risk of bias from performance or
 interpretation of the serological test in 73%
 (36/49). Only 10% (4/40) of studies included
 outpatients. Only two studies evaluated tests at
 the point of care. For each method of testing,
 pooled sensitivity and specificity were not
 associated with the immunoglobulin class measured.
 The pooled sensitivity of ELISAs measuring IgG or
 IgM was 84.3% (95% confidence interval 75.6% to
 90.9%), of LFIAs was 66.0% (49.3% to 79.3%), and
 of CLIAs was 97.8% (46.2% to 100%). In all
 analyses, pooled sensitivity was lower for LFIAs,
 the potential point-of-care method. Pooled
 specificities ranged from 96.6% to 99.7%. Of the
 samples used for estimating specificity, 83%
 (10 465/12 547) were from populations tested
 before the epidemic or not suspected of having
 covid-19. Among LFIAs, pooled sensitivity of
 commercial kits (65.0%, 49.0% to 78.2%) was lower
 than that of non-commercial tests (88.2%, 83.6% to
 91.3%). Heterogeneity was seen in all analyses.
 Sensitivity was higher at least three weeks after
 symptom onset (ranging from 69.9% to 98.9%)
 compared with within the first week (from 13.4% to
 50.3%). Conclusion Higher quality clinical studies assessing the
 diagnostic accuracy of serological tests for
 covid-19 are urgently needed. Currently, available
 evidence does not support the continued use of
 existing point-of-care serological tests. Study registration PROSPERO CRD42020179452.

https://www.bmj.com/content/bmj/370/bmj.m2516.full.pdf

Diagnostic accuracy of serological tests for covid-19: systematic review and meta-analysis.

SARS-CoV-2 immunity: review and applications to phase 3 vaccine candidates.

Background Timely diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a prerequisite for treatment and prevention. The serology characteristics and complement diagnosis value of the antibody test to RNA test need to be demonstrated. Method Serial sera of 80 patients with PCR-confirmed coronavirus disease 2019 (COVID-19) were collected at the First Affiliated Hospital of Zhejiang University, Hangzhou, China. Total antibody (Ab), IgM and IgG antibodies against SARS-CoV-2 were detected, and the antibody dynamics during the infection were described. Results The seroconversion rates for Ab, IgM and IgG were 98.8%, 93.8% and 93.8%, respectively. The first detectible serology marker was Ab, followed by IgM and IgG, with a median seroconversion time of 15, 18 and 20 days post exposure (d.p.e.) or 9, 10 and 12 days post onset (d.p.o.), respectively. The antibody levels increased rapidly beginning at 6 d.p.o. and were accompanied by a decline in viral load. For patients in the early stage of illness (0–7 d.p.o), Ab showed the highest sensitivity (64.1%) compared with IgM and IgG (33.3% for both; p Conclusions A typical acute antibody response is induced during SARS-CoV-2 infection. Serology testing provides an important complement to RNA testing in the later stages of illness for pathogenic-specific diagnosis and helpful information to evaluate the adapted immunity status of patients.

https://erj.ersjournals.com/content/erj/56/2/2000763.full.pdf

Xue Jie Zhang

Papers

Serology characteristics of SARS-CoV-2 infection after exposure and post-symptom onset.