The durability of natural infection and vaccine-induced immunity against future infection by SARS-CoV-2

The durability of vaccine-mediated immunity to SARS-CoV-2, the durations to breakthrough infection, and the optimal timings of booster vaccination are crucial knowledge for pandemic response. Here, we applied comparative evolutionary analyses to estimate the durability of immunity and the likelihood of breakthrough infections over time following vaccination by BNT162b2 (Pfizer-BioNTech), mRNA-1273 (Moderna), ChAdOx1 (Oxford-AstraZeneca), and Ad26.COV2.S (Johnson & Johnson/Janssen). We evaluated anti-Spike (S) immunoglobulin G (IgG) antibody levels elicited by each vaccine relative to natural infection. We estimated typical trajectories of waning and corresponding infection probabilities, providing the distribution of times to breakthrough infection for each vaccine under endemic conditions. Peak antibody levels elicited by messenger RNA (mRNA) vaccines mRNA-1273 and BNT1262b2 exceeded that of natural infection and are expected to typically yield more durable protection against breakthrough infections (median 29.6 mo; 5 to 95% quantiles 10.9 mo to 7.9 y) than natural infection (median 21.5 mo; 5 to 95% quantiles 3.5 mo to 7.1 y). Relative to mRNA-1273 and BNT1262b2, viral vector vaccines ChAdOx1 and Ad26.COV2.S exhibit similar peak anti-S IgG antibody responses to that from natural infection and are projected to yield lower, shorter-term protection against breakthrough infection (median 22.4 mo and 5 to 95% quantiles 4.3 mo to 7.2 y; and median 20.5 mo and 5 to 95% quantiles 2.6 mo to 7.0 y; respectively). These results leverage the tools from evolutionary biology to provide a quantitative basis for otherwise unknown parameters that are fundamental to public health policy decision-making.

The unprecedented development of efficacious vaccines against SARS-CoV-2 has represented a triumph in the global effort to control the ongoing COVID-19 pandemic. Vaccines have been shown to provide short-term protection from major adverse health outcomes of hospitalization and death (1–4). However, protection against breakthrough infection wanes (5), and breakthroughs have been extensively documented (6, 7). In response, the Food and Drug Administration advisory committee has recommended a booster of the Pfizer-BioNTech and Moderna vaccines at least 5 mo after completion of the primary series to people ≥12 and ≥18 y of age, respectively (8). A booster dose of the Johnson & Johnson/Janssen vaccine has been authorized on a faster timescale—as early as 2 mo after the single dose to individuals 18 y of age and older (8). Nevertheless, the optimal timing of boosting remains challenging to assess. Consequently, rigorous prediction of the durability of immunity conferred by vaccination against the SARS-CoV-2 virus is essential to personal and public health decision-making, having major implications regarding policy decisions about COVID-19 vaccination around the world (9, 10).Short-term longitudinal studies of SARS-CoV-2-neutralizing antibodies in vaccinated individuals (11–13) can provide information crucial to our understanding of the durability of vaccine-mediated immunity. Peak antibody responses following vaccination versus natural responses have also been quantified (14), facilitating analytical comparison of initial immune responses. For endemic viruses, longitudinal data on reinfection can provide reinfection probabilities associated with antibody level. However, longitudinal data on SARS-CoV-2 reinfection are not available during the short term associated with pandemic spread. Nevertheless, longitudinal reinfection data for a diversity of coronaviruses have been collected (15–20). SARS-CoV-2 reinfection probabilities have been obtained from them by phylogenetic analysis, using continuous ancestral and descendent state estimation (21). These estimates, produced before reinfection was commonplace, proved accurate (predicting an 18% probability of reinfection at ∼270 d [ref. 21] that was validated by a subsequent empirical finding of 18% reinfection by 275 to 300 d after primary infection [ref. 22] and, likewise, predicting a 34% probability of reinfection at ∼450 d after primary infection [ref. 21] that was validated by a subsequent empirical finding of 34% breakthrough infection 420 to 480 d after primary vaccination [ref. 23]). Similar analyses pairing antibody response and rates of waning for each vaccine with infection probabilities can enable quantification of the durability of vaccine-mediated immunity against breakthrough infections. The aim of this study is to leverage data on antibody response to each vaccine and corresponding probabilities of infection to estimate the durability of vaccine-mediated immunity against breakthrough SARS-CoV-2 infection for four well-studied vaccines: mRNA-1273, BNT162b2, ChAdOx1, and Ad26.COV2.S.     

Paediatric gastrointestinal disorders in SARS-CoV-2 infection: Epidemiological and clinical implications

The coronavirus disease 2019 (COVID-19) pandemic is a threat worldwide for individuals of all ages, including children. Gastrointestinal manifestations could be the initial presenting manifestation in many patients, especially in children. These symptoms are more common in patients with severe disease than in patients with non-severe disease. Approximately 48.1% of patients had a stool sample that was positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral RNA. Children typically form 1%-8% of all laboratory-confirmed cases of SARS-CoV-2. Gastrointestinal manifestations of COVID-19 in children are not rare, with a prevalence between 0 and 88%, and a wide variety of presentations, including diarrhoea, vomiting, and abdominal pain, can develop before, with or after the development of respiratory symptoms. Atypical manifestations such as appendicitis or liver injury could also appear, especially in the presence of multisystem inflammatory disease. In this review, we discussed the epidemiology of COVID-19 gastrointestinal diseases in children as well as their implications on the diagnosis, misdiagnosis, prognosis, and faecal-oral transmission route of COVID-19 and the impact of gastrointestinal diseases on the gut microbiome, child nutrition, and disease management.     

Increased transmissibility and global spread of SARS-CoV-2 variants of concern as at June 2021

We present a global analysis of the spread of recently emerged SARS-CoV-2 variants and estimate changes in effective reproduction numbers at country-specific level using sequence data from GISAID. Nearly all investigated countries demonstrated rapid replacement of previously circulating lineages by the World Health Organization-designated variants of concern, with estimated transmissibility increases of 29% (95% CI: 24–33), 25% (95% CI: 20–30), 38% (95% CI: 29–48) and 97% (95% CI: 76–117), respectively, for B.1.1.7, B.1.351, P.1 and B.1.617.2.     

Co-infection of SARS-CoV-2 and dengue virus: a clinical challenge

Many regions of the world where dengue epidemics are seasonal are also facing the COVID-19 pandemic. This is a medical concern because both diseases are difficult to distinguish since they have similar clinical symptoms and laboratory findings, and because they have different clinical management. So far, co-infection of SARS-CoV-2 and dengue virus (DENV) has not been studied. Herein we report the first case of a patient with co-infection of COVID-19 and dengue. Both infections were simultaneously laboratory confirmed by positive RT-qPCR for SARS-CoV-2 and RT-qPCR for DENV, NS1, IgM and IgG antibody tests for dengue. The patient had a favorable clinical improvement, without severe symptoms. This case emphasize that, in pandemic era, having a diagnostic of one infection does not rule out the possibility of having another infection concomitantly. In addition, underscores the importance of an accurate and timely diagnosis to prevent the spread of COVID-19.     

Assessment of population infection with SARS-CoV-2 in Ontario,Canada, March to June 2020

BackgroundSerosurveys for SARS-CoV-2 aim to estimate the proportion of the population that has been infected.AimThis observational study assesses the seroprevalence of SARS-CoV-2 antibodies in Ontario, Canada during the first pandemic wave.MethodsUsing an orthogonal approach, we tested 8,902 residual specimens from the Public Health Ontario laboratory over three time periods during March–June 2020 and stratified results by age group, sex and region. We adjusted for antibody test sensitivity/specificity and compared with reported PCR-confirmed COVID-19 cases.ResultsAdjusted seroprevalence was 0.5% (95% confidence interval (CI): 0.1–1.5) from 27 March–30 April, 1.5% (95% CI: 0.7–2.2) from 26–31 May, and 1.1% (95% CI: 0.8–1.3) from 5–30 June 2020. Adjusted estimates were highest in individuals aged ≥ 60 years in March–April (1.3%; 95% CI: 0.2–4.6), in those aged 20–59 years in May (2.1%; 95% CI: 0.8–3.4) and in those aged ≥ 60 years in June (1.6%; 95% CI: 1.1–2.1). Regional seroprevalence varied, and was highest for Toronto in March–April (0.9%; 95% CI: 0.1–3.1), for Toronto in May (3.2%; 95% CI: 1.0–5.3) and for Toronto (1.5%; 95% CI: 0.9–2.1) and Central East in June (1.5%; 95% CI: 1.0–2.0). We estimate that COVID-19 cases detected by PCR in Ontario underestimated SARS-CoV-2 infections by a factor of 4.9.ConclusionsOur results indicate low population seroprevalence in Ontario, suggesting that public health measures were effective at limiting the spread of SARS-CoV-2 during the first pandemic wave.     

Assessing the Impact of SARS-CoV-2 Lineages and Mutations on Patient Survival

Objectives: More than two years into the COVID-19 pandemic, SARS-CoV-2 still remains a global public health problem. Successive waves of infection have produced new SARS-CoV-2 variants with new mutations for which the impact on COVID-19 severity and patient survival is uncertain. Methods: A total of 764 SARS-CoV-2 genomes, sequenced from COVID-19 patients, hospitalized from 19th February 2020 to 30 April 2021, along with their clinical data, were used for survival analysis. Results: A significant association of B.1.1.7, the alpha lineage, with patient mortality (log hazard ratio (LHR) = 0.51, C.I. = [0.14,0.88]) was found upon adjustment by all the covariates known to affect COVID-19 prognosis. Moreover, survival analysis of mutations in the SARS-CoV-2 genome revealed 27 of them were significantly associated with higher mortality of patients. Most of these mutations were located in the genes coding for the S, ORF8, and N proteins. Conclusions: This study illustrates how a combination of genomic and clinical data can provide solid evidence for the impact of viral lineage on patient survival.     

Impact of the Omicron variant on SARS-CoV-2 reinfections in France,March 2021 to February 2022

Since the first reports in summer 2020, SARS-CoV-2 reinfections have raised concerns about the immunogenicity of the virus, which will affect SARS-CoV-2 epidemiology and possibly the burden of COVID-19 on our societies in the future. This study provides data on the frequency and characteristics of possible reinfections, using the French national COVID-19 testing database. The Omicron variant had a large impact on the frequency of possible reinfections in France, which represented 3.8% of all confirmed COVID-19 cases since December 2021.     

Analysis of SARS-CoV-2 infection dynamic in vivo using reporter-expressing viruses

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the current COVID-19 pandemic, is one of the biggest threats to public health. However, the dynamic of SARS-CoV-2 infection remains poorly understood. Replication-competent recombinant viruses expressing reporter genes provide valuable tools to investigate viral infection. Low levels of reporter gene expressed from previous reporter-expressing recombinant (r)SARS-CoV-2 in the locus of the open reading frame (ORF)7a protein have jeopardized their use to monitor the dynamic of SARS-CoV-2 infection in vitro or in vivo. Here, we report an alternative strategy where reporter genes were placed upstream of the highly expressed viral nucleocapsid (N) gene followed by a porcine tescherovirus (PTV-1) 2A proteolytic cleavage site. The higher levels of reporter expression using this strategy resulted in efficient visualization of rSARS-CoV-2 in infected cultured cells and excised lungs or whole organism of infected K18 human angiotensin converting enzyme 2 (hACE2) transgenic mice. Importantly, real-time viral infection was readily tracked using a noninvasive in vivo imaging system and allowed us to rapidly identify antibodies which are able to neutralize SARS-CoV-2 infection in vivo. Notably, these reporter-expressing rSARS-CoV-2, in which a viral gene was not deleted, not only retained wild-type (WT) virus-like pathogenicity in vivo but also exhibited high stability in vitro and in vivo, supporting their use to investigate viral infection, dissemination, pathogenesis, and therapeutic interventions for the treatment of SARS-CoV-2 in vivo.

Coronaviruses (CoVs) are enveloped, single-stranded, positive-sense RNA viruses that belong to the Coronaviridae family that can cause mild to severe respiratory infections in humans (1). Two CoVs have been associated with severe respiratory syndrome in the past two decades: severe acute respiratory syndrome CoV (SARS-CoV) in 2002–2003 and Middle East respiratory syndrome CoV (MERS-CoV) in 2012 to the present (2). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in the Chinese city of Wuhan in December 2019 and is the causative agent of the COVID-19 pandemic (3, 4). As of June 2021, SARS-CoV-2 has been reported to be responsible for over 150 million human infection cases and more than 3 million deaths around the World (https://covid19.who.int/).Like SARS-CoV and MERS-CoV, SARS-CoV-2 mainly replicates in the upper (nasal turbinate) and lower (lungs) respiratory tract, resulting, in some cases, in fatal respiratory illness (5, 6). However, the intrahost dissemination and pathogenesis of SARS-CoV-2 are not well understood. Several animal models of SARS-CoV-2 infection have been established and have already provided very valuable information to understand the mechanism of tissue and cell tropism, replication, and pathogenesis (7–11). However, assessing the presence of SARS-CoV-2 in infected animals, organs, or tissues has required collection and processing of samples upon euthanasia, which complicates studies examining the longitudinal dynamic of a viral infection within an infected host. Recombinant (r)SARS-CoV-2 expressing reporter genes could overcome this problem and allow tracking of viral infection in vivo and in real time by monitoring the expression of the reporter gene. We and others have documented the feasibility of generating reporter-expressing rSARS-CoV-2 using a reverse genetic system (12, 13). These rSARS-CoV-2 have been genetically engineered to express the reporter gene by substituting the viral open reading frame (ORF) 7a protein with the reporter gene of interest, an experimental approach first employed to generate reporter-expressing rSARS-CoV (14). Despite these reporter-expressing rSARS-CoV-2 showing plaque phenotype, replication, and growth kinetics comparable to those of wild-type virus (rSARS-CoV-2/WT) in vitro (12, 13, 15), it is unclear whether the reporter-expressing rSARS-CoV-2 lacking ORF7a recapitulate viral pathogenicity in vivo and whether reporter gene expression levels could be efficiently tracked ex vivo using tissues or organs from infected animals, or in a whole organism in vivo.In this study, we cloned fluorescent (Venus) and luciferase (Nano luciferase, Nluc) reporter genes upstream of the SARS-CoV-2 nucleocapsid (N) gene separated by the porcine tescherovirus (PTV-1) 2A proteolytic cleavage site to generate new reporter-expressing rSARS-CoV-2 without the deletion of the ORF7a protein. In vitro, rSARS-CoV-2 expressing reporter genes from the viral N locus replicated and made viral plaques similar to those of rSARS-CoV-2/WT. Reporter-expressing rSARS-CoV-2 generated using this 2A strategy expressed higher levels of reporter gene expression compared to those rSARS-CoV-2 generated by substituting the viral ORF7a protein with the reporter gene of interest. Importantly, rSARS-CoV-2/Venus-2A and rSARS-CoV-2/Nluc-2A showed rSARS-CoV-2/WT−like pathogenicity in vivo. The higher level of Venus expression from rSARS-CoV-2/Venus-2A allowed us to detect viral infection in the lungs of infected K18 human angiotensin converting enzyme 2 (hACE2) transgenic mice using an in vivo imaging system (IVIS). Moreover, Venus expression from rSARS-CoV-2/Venus-2A was stable up to seven passages in vitro in cultured Vero E6 cells and in vivo up to day 6 postinfection. Importantly, levels of Venus expression correlated well with viral titers detected in the lungs, demonstrating the feasibility of using Venus expression as a valid surrogate marker to evaluate SARS-CoV-2 infection. Using rSARS-CoV-2/Nluc-2A, we were able to track the dynamic of viral infection in real time and longitudinally assess SARS-CoV-2 infection in vivo. Finally, we testified to the feasibility of using the rSARS-CoV-2/Nluc-2A to rapidly and accurately identify antibodies that neutralize viral infection in vivo.Our data demonstrate that these next-generation rSARS-CoV-2 expressing reporter genes we have generated can be used to easily monitor viral infection in cultured cells and in validated animal models of infection. Importantly, our new rSARS-CoV-2/Venus-2A or rSARS-CoV-2/Nluc-2A retain similar virulence to that of rSARS-CoV-2/WT in K18 hACE2 transgenic mice and can be used to investigate viral replication, tropism, and viral dissemination and pathogenesis in vivo and to rapidly identify therapeutics for the treatment of SARS-CoV-2 infection and associated COVID-19 disease.     

Dysregulated liver function in SARS-CoV-2 infection: Current understanding and perspectives

Since it was first reported in December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has spread rapidly around the world to cause the ongoing pandemic. Although the clinical manifestations of SARS-CoV-2 infection are predominantly in the respiratory system, liver enzyme abnormalities exist in around half of the cases, which indicate liver injury, and raise clinical concern. At present, there is no consensus whether the liver injury is directly caused by viral replication in the liver tissue or indirectly by the systemic inflammatory response. This review aims to summarize the clinical manifestations and to explore the underlying mechanisms of liver dysfunction in patients with SARS-CoV-2 infection.     

Hyponatremia and SARS-CoV-2 infection: A narrative review

A novel rapid spreading and changing virus called SARS-CoV-2 appeared in Wuhan city in December 2019. It was announced by the World Health Organization (WHO) as a pandemic disease in March 2020. It commonly presents with respiratory symptoms; however, it may be asymptomatic. Electrolyte abnormalities are not uncommon features of SARS-CoV-2 infection. Hyponatremia is one of these electrolyte disturbances among SARS-CoV-2 patients, and it may produce symptoms such as weakness and seizure as the initial presenting symptoms. The underlying mechanism(s) of hyponatremia due to SARS-CoV-2 infection is (are) not established.The aim of this review is to evaluate the possible mechanism of hyponatremia in patients with COVID-19. Understanding and categorizing the hyponatremia in these patients will lead to better treatment and correction of the hyponatremia.A review of the literature between December 2019 and March 2022 was conducted searching for the possible reported mechanism(s) of hyponatremia in SARS-CoV-2.Although SIADH is the commonly reported cause of hyponatremia in SARS-CoV-2 infection, other causes such as diarrhea, vomiting, and kidney salt loss must be considered before SIADH.     

Impact of outpatient SARS-CoV-2 infections in minority children

Data regarding COVID-19 in the adult population and hospitalized children is rapidly evolving, but little is known about children infected with severe acute respiratory syndrome coronavirus 2 who do not require hospitalization.In an observational, retrospective study we analyzed risk factors, demographics and clinical course of non-hospitalized patients ≤ 21 years of age with COVID-19 infection.Of the 1,796 patients evaluated, 170 were infected, and 40 participated in a telephone survey. Children older >10 years of age (OR: 2.19), Hispanic ethnicity (OR: 3) and residing in counties with higher rates of poverty (OR: 1.5) were associated with higher risk of infection, while older girls were more likely to experience prolonged duration of symptoms (median: 32 days). Consistent with prior reports, fever and cough were present in most of our patients. Shortness of breath, diarrhea, anosmia, and ageusia were more common in our outpatient population than previously reported.Larger studies addressing the clinical and psychosocial impact of CoVID-19 infection in children living in high-risk environments are warranted.     

无锡SARS-CoV-2病例的流行病学和临床复阳评价

目的 通过分析无锡新型冠状病毒肺炎(SARS-CoV-2)的传播关系、临床分级和复阳病例的临床表现评价本地病毒的传播及致病性特征.方法 以2020年1月23日至11月20日无锡市第五人民医院收治的SARS-CoV-2阳性病例为研究对象,通过分析传播的流行病学及复阳病例的临床特征,初步评价病毒的传播及致病性特征.结果 C...     

Case Study of Two Post Vaccination SARS-CoV-2 Infections with P1 Variants in CoronaVac Vaccinees in Brazil

The rapid development of efficacious and safe vaccines against coronavirus disease 2019 (COVID-19) has been instrumental in mitigating the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Moreover, the emergence of SARS-CoV-2 variants raised concerns on the efficacy of these vaccines. Herein, we report two cases of breakthrough infections with the P1 variant in patients vaccinated with CoronaVac, which is one of the two vaccines authorized for emergency use in the Brazilian immunization program. Our observations suggest that the vaccine reduced the severity of the disease and highlight the potential risk of illness following vaccination and subsequent infection with the P1 variant as well as for continued efforts to prevent and diagnose infection in vaccinated persons.