Booster Vaccination with BNT162b2 Improves Cellular and Humoral Immune Response in the Pediatric Population Immunized with CoronaVac (preprint)

The SARS-CoV-2 Omicron variant and its sublineages continue to cause COVID-19—associated pediatric hospitalizations, severe disease, and death globally. BNT162b2 and CoronaVac are among the top most widely used COVID-19 vaccines. Much less is known on the Wuhan-Hu-1 strain based vaccines in the pediatric population compared to adults. Given the worldwide need for booster vaccinations to stimulate the immune response against new Omicron variants of SARS-CoV-2, we characterized the humoral and cellular immune response against Omicron variant BA.1 in a pediatric population aged 10 to 16 years who received heterologous vaccination based on two doses CoronaVac, two doses CoronaVac (2x) plus one booster doses BNT162b2 [CoronaVac(2x) + BNT162b2 (1x)], two doses CoronaVac plus two booster doses BNT162b2 [CoronaVac(2x) + BNT162b2 (2x)], and three doses BNT162b2. We observed that [CoronaVac(2x) + BNT162b2 (2x)] vaccination showed higher anti-S1 and neutralizing antibody titers and CD4 and CD8 T cell immunity specific to the Omicron variant compared to immunization with two doses CoronaVac alone. Furthermore, from all groups tested, immunity against Omicron was highest in individuals who received three doses BNT162b2. We conclude that booster vaccination with BNT162b2 promotes greater immunity against SARS-CoV-2 in the pediatric population compared to two doses CoronaVac alone.

Excess risk of SARS-CoV-2 infection among in-person nonhealthcare workers in six states, September 2020-June 2021.

BACKGROUND: While the occupational risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection for healthcare personnel in the United States has been relatively well characterized, less information is available on the occupational risk for workers employed in other settings. Even fewer studies have attempted to compare risks across occupations and industries. Using differential proportionate distribution as an approximation, we evaluated excess risk of SARS-CoV-2 infection by occupation and industry among non-healthcare workers in six states. METHODS: We analyzed data on occupation and industry of employment from a six-state callback survey of adult non-healthcare workers with confirmed SARS-CoV-2 infection and population-based reference data on employment patterns, adjusted for the effect of telework, from the U.S. Bureau of Labor Statistics. We estimated the differential proportionate distribution of SARS-CoV-2 infection by occupation and industry using the proportionate morbidity ratio (PMR). RESULTS: Among a sample of 1111 workers with confirmed SARS-CoV-2 infection, significantly higher-than-expected proportions of workers were employed in service occupations (PMR 1.3, 99% confidence interval [CI] 1.1-1.5) and in the transportation and utilities (PMR 1.4, 99% CI 1.1-1.8) and leisure and hospitality industries (PMR 1.5, 99% CI 1.2-1.9). CONCLUSIONS: We found evidence of significant differences in the proportionate distribution of SARS-CoV-2 infection by occupation and industry among respondents in a multistate, population-based survey, highlighting the excess risk of SARS-CoV-2 infection borne by some worker populations, particularly those whose jobs require frequent or prolonged close contact with other people.

Prolonged Elevations of Factor VIII and von Willebrand Factor Antigen After Multisystem Inflammatory Syndrome in Children.

Multisystem Inflammatory Syndrome in Children (MIS-C) is a late systemic inflammatory response to a recent mild or asymptomatic coronavirus disease of 2019 infection. The pathophysiology is incompletely understood but it often features significant coagulopathy along with cardiac and endothelial dysfunction. Endothelial inflammation has been primarily described in acute coronavirus disease of 2019 infection, with less characterization in MIS-C. Here we describe novel findings of nearly universal severe and prolonged factor VIII (FVIII) and von Willebrand factor antigen elevations in an institutional cohort of patients with MIS-C ages younger than or 21 years old (N=31). All patients had elevated acute phase reactants and D-dimer at presentation and met published criteria for MIS-C. FVIII was high at presentation in 97% of patients but continued to rise during the ensuing weeks of treatment to a mean 429%, peaking on median day 17 of illness as an outpatient. FVIII levels were >600% in multiple patients. von Willebrand factor antigen was measured less frequently but showed similar trends. These escalations occurred amidst resolving cardiac dysfunction and acute phase reactant normalization and despite patients receiving multimodal anti-inflammatory treatments and aspirin and enoxaparin thromboprophylaxis. No thrombotic events occurred. Endothelial dysfunction represented by very elevated FVIII levels may persist longer than other acute phase reactants may reflect.

Potential Benefit of Vitamin D Supplementation in COVID-19.

Vitamin D is an important nutrient in the body that plays a vital role in immune system function. Several epidemiologic studies have shown that low vitamin D levels are found in a large percentage of COVID-19 patients with acute respiratory failure and that vitamin D levels may predict mortality in COVID-19 infection. Based on these findings, vitamin D supplementation may be an effective approach to preventing and/or treating COVID-19. Potential underlying mechanisms and clinical trial data evaluating the impact of supplementation in humans are described below.

COVID-19 Outbreaks Linked to Workplaces, 23 US Jurisdictions, August-October 2021.

OBJECTIVES: Early in the COVID-19 pandemic, several outbreaks were linked with facilities employing essential workers, such as long-term care facilities and meat and poultry processing facilities. However, timely national data on which workplace settings were experiencing COVID-19 outbreaks were unavailable through routine surveillance systems. We estimated the number of US workplace outbreaks of COVID-19 and identified the types of workplace settings in which they occurred during August-October 2021. METHODS: The Centers for Disease Control and Prevention collected data from health departments on workplace COVID-19 outbreaks from August through October 2021: the number of workplace outbreaks, by workplace setting, and the total number of cases among workers linked to these outbreaks. Health departments also reported the number of workplaces they assisted for outbreak response, COVID-19 testing, vaccine distribution, or consultation on mitigation strategies. RESULTS: Twenty-three health departments reported a total of 12 660 workplace COVID-19 outbreaks. Among the 12 470 workplace types that were documented, 35.9% (n = 4474) of outbreaks occurred in health care settings, 33.4% (n = 4170) in educational settings, and 30.7% (n = 3826) in other work settings, including non-food manufacturing, correctional facilities, social services, retail trade, and food and beverage stores. Eleven health departments that reported 3859 workplace outbreaks provided information about workplace assistance: 3090 (80.1%) instances of assistance involved consultation on COVID-19 mitigation strategies, 1912 (49.5%) involved outbreak response, 436 (11.3%) involved COVID-19 testing, and 185 (4.8%) involved COVID-19 vaccine distribution. CONCLUSIONS: These findings underscore the continued impact of COVID-19 among workers, the potential for work-related transmission, and the need to apply layered prevention strategies recommended by public health officials.

Pregnancy and infant outcomes by trimester of SARS-CoV-2 infection in pregnancy-SET-NET, 22 jurisdictions, January 25, 2020-December 31, 2020.

OBJECTIVES: We describe clinical characteristics, pregnancy, and infant outcomes in pregnant people with laboratory-confirmed SARS-CoV-2 infection by trimester of infection. STUDY DESIGN: We analyzed data from the Surveillance for Emerging Threats to Mothers and Babies Network and included people with infection in 2020, with known timing of infection and pregnancy outcome. Outcomes are described by trimester of infection. Pregnancy outcomes included live birth and pregnancy loss (<20 weeks and ≥20 weeks gestation). Infant outcomes included preterm birth (<37 weeks gestation), small for gestational age, birth defects, and neonatal intensive care unit admission. Adjusted prevalence ratios (aPR) were calculated for pregnancy and selected infant outcomes by trimester of infection, controlling for demographics. RESULTS: Of 35,200 people included in this analysis, 50.8% of pregnant people had infection in the third trimester, 30.8% in the second, and 18.3% in the first. Third trimester infection was associated with a higher frequency of preterm birth compared to first or second trimester infection combined (17.8% vs. 11.8%; aPR 1.44 95% CI: 1.35-1.54). Prevalence of birth defects was 553.4/10,000 live births, with no difference by trimester of infection. CONCLUSIONS: There were no signals for increased birth defects among infants in this population relative to national baseline estimates, regardless of timing of infection. However, the prevalence of preterm birth in people with SARS-CoV-2 infection in pregnancy in our analysis was higher relative to national baseline data (10.0-10.2%), particularly among people with third trimester infection. Consequences of COVID-19 during pregnancy support recommended COVID-19 prevention strategies, including vaccination.

Nirmatrelvir Resistance in SARS-CoV-2 Omicron_BA.1 and WA1 Replicons and Escape Strategies (preprint)

The antiviral component of Paxlovid, nirmatrelvir (NIR), forms a covalent bond with Cys145 of SARS-CoV-2 nsp5. To explore NIR resistance we designed mutations to impair binding of NIR over substrate. Using 12 Omicron (BA.1) and WA.1 SARS-CoV-2 replicons, cell-based complementation and enzymatic assays, we showed that in both strains, E166V imparted high NIR resistance (~55-fold), with major decrease in WA1 replicon fitness (~20-fold), but not BA.1 (~2-fold). WA1 replicon fitness was restored by L50F. These differences may contribute to a potentially lower barrier to resistance in Omicron than WA1. E166V is rare in untreated patients, albeit more prevalent in paxlovid-treated EPIC-HR clinical trial patients. Importantly, NIR-resistant replicons with E166V or E166V/L50F remained susceptible to a) the flexible GC376, and b) PF-00835231, which forms additional interactions. Molecular dynamics simulations show steric clashes between the rigid and bulky NIR t-butyl and {beta}-branched V166 distancing the NIR warhead from its Cys145 target. In contrast, GC376, through-wiggling and jiggling- accommodates V166 and still covalently binds Cys145. PF-00835231 uses its strategically positioned methoxy-indole to form a beta-sheet and overcome E166V. Drug design based on strategic flexibility and main chain-targeting may help develop second-generation nsp5-targeting antivirals efficient against NIR-resistant viruses.

The longitudinal impact of the COVID-19 pandemic on health behaviors, psychosocial factors, and cognitive functioning in older adults.

Background: Older adults are at a greater risk for contracting and experiencing severe illness from COVID-19 and may be further affected by pandemic-related precautions (e.g., social distancing and isolation in quarantine). However, the longitudinal impact of the COVID-19 pandemic on older adults is unclear. The current study examines changes in health behaviors, psychosocial factors, and cognitive functioning in a large sample of older adults using a pre-pandemic baseline and longitudinal follow-up throughout 9 months of the COVID-19 pandemic. Methods: One hundred and eighty-nine older adults (ages 65-89) were recruited from a multisite clinical trial to complete additional virtual assessments during the COVID-19 pandemic. Mixed effects models evaluated changes in health behaviors, psychosocial factors, and cognitive functioning during the pandemic compared to a pre-pandemic baseline and over the course of the pandemic (i.e., comparing the first and last COVID-19 timepoints). Results: Compared to their pre-pandemic baseline, during the pandemic, older adults reported worsened sleep quality, perceived physical health and functioning, mental health, slight increases in depression and apathy symptoms, reduced social engagement/perceived social support, but demonstrated better performance on objective cognitive tasks of attention and working memory. Throughout the course of the pandemic, these older adults reported continued worsening of perceived physical health and function, fewer depression symptoms, and they demonstrated improved cognitive performance. It is important to note that changes on self-report mood measures and cognitive performance were relatively small regarding clinical significance. Education largely served as a protective factor, such that greater years of education was generally associated with better outcomes across domains. Conclusions: The present study provides insights into the longitudinal impact of the COVID-19 pandemic on health behaviors, psychosocial factors, and cognitive functioning in a population disproportionately affected by the virus. Replicating this study design in a demographically representative older adult sample is warranted to further inform intervention strategies targeting older adults negatively impacted by the COVID-19 pandemic.

Six-Month Outcomes of Infants Born to People With SARS-CoV-2 in Pregnancy.

OBJECTIVES: To assess the 6-month incidence of laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, postnatal care, hospitalization, and mortality among infants born to people with laboratory-confirmed SARS-CoV-2 infection during pregnancy by timing of maternal infection. METHODS: Using a cohort of liveborn infants from pregnancies with SARS-CoV-2 infections in the year 2020 from 10 United States jurisdictions in the Surveillance for Emerging Threats to Mother and Babies Network, we describe weighted estimates of infant outcomes from birth through 6 months of age from electronic health and laboratory records. RESULTS: Of 6601 exposed infants with laboratory information through 6 months of age, 1.0% (95% confidence interval: 0.8-1.1) tested positive, 19.1% (17.5-20.6) tested negative, and 80.0% (78.4-81.6) were not known to be tested for SARS-CoV-2. Among those ≤14 days of age, SARS-CoV-2 infection occurred only with maternal infection ≤14 days before delivery. Of 3967 infants with medical record abstraction, breastmilk feeding initiation was lower when maternal infection occurred ≤14 days before delivery compared with >14 days (77.6% [72.5-82.6] versus 88.3% [84.7-92.0]). Six-month all-cause hospitalization was 4.1% (2.0-6.2). All-cause mortality was higher among infants born to people with infection ≤14 days (1.0% [0.4-1.6]) than >14 days (0.3% [0.1-0.5]) before delivery. CONCLUSIONS: Results are reassuring, with low incidences of most health outcomes examined. Incidence of infant SARS-CoV-2, breastmilk feeding initiation, and all-cause mortality differed by timing of maternal infection. Strategies to prevent infections and support pregnant people with coronavirus disease 2019 may improve infant outcomes.

Reported Exposures Among In-Person Workers With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection in 6 States, September 2020-June 2021.

BACKGROUND: Surveillance systems lack detailed occupational exposure information from workers with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The National Institute for Occupational Safety and Health partnered with 6 states to collect information from adults diagnosed with SARS-CoV-2 infection who worked in person (outside the home) in non-healthcare settings during the 2 weeks prior to illness onset. METHODS: The survey captured demographic, medical, and occupational characteristics and work- and non-work-related risk factors for SARS-CoV-2 infection. Reported close contact with a person known or suspected to have SARS-CoV-2 infection was categorized by setting as exposure at work, exposure outside of work only, or no known exposure/did not know. Frequencies and percentages of exposure types are compared by respondent characteristics and risk factors. RESULTS: Of 1111 respondents, 19.4% reported exposure at work, 23.4% reported exposure outside of work only, and 57.2% reported no known exposure/did not know. Workers in protective service occupations (48.8%) and public administration industries (35.6%) reported exposure at work most often. More than one third (33.7%) of respondents who experienced close contact with ≥10 coworkers per day and 28.8% of respondents who experienced close contact with ≥10 customers/clients per day reported exposures at work. CONCLUSIONS: Exposure to occupational SARS-CoV-2 was common among respondents. Examining differences in exposures among different worker groups can help identify populations with the greatest need for prevention interventions. The benefits of recording employment characteristics as standard demographic information will remain relevant as new and reemerging public health issues occur.

Test-retest reliability of a new assessment to detect detailed temporal patterns of polysubstance use.

OBJECTIVE: While polysubstance use is highly prevalent among people who use drugs, the field lacks a reliable assessment that can detect detailed temporal patterns of polysubstance use. This study assessed the test-retest reliability of the newly developed Polysubstance Use-Temporal Patterns Section (PSU-TPS). METHODS: Participants who used cocaine plus alcohol and/or marijuana at least once in the past 30 days (n = 48) were interviewed at baseline and approximately 7 days later (retest) using the Substance Abuse Module and the PSU-TPS. Reliability of PSU-TPS measures of quantity, frequency, and duration of polysubstance use was examined using intra-class correlation coefficients (ICCs) and kappa tests. RESULTS: Excellent reliability was observed for frequencies of concurrent polysubstance use patterns in the past 30 days (ICC range: 0.90-0.94) and quantity of alcohol use (ICC = 0.83), and fair to good reliability was observed for duration of substance use (ICC range: 0.52-0.73). CONCLUSION: Detailed information regarding cocaine, alcohol, and marijuana polysubstance use in the past 30 days can be reliably measured with the PSU-TPS. Data on the order and timing of polysubstance use at the hourly level will improve our understanding of the implications of sequential and simultaneous use patterns, which can help inform treatment and prevention efforts.

Population-based hospitalization burden estimates for respiratory viruses, 2015-2019.

BACKGROUND: Acute respiratory infections (ARIs) result in millions of illnesses and hundreds of thousands of hospitalizations annually in the United States. The responsible viruses include influenza, parainfluenza, human metapneumovirus, coronaviruses, respiratory syncytial virus (RSV), and human rhinoviruses. This study estimated the population-based hospitalization burden of those respiratory viruses (RVs) over 4 years, from July 1, 2015 to June 30, 2019, among adults ≥18 years of age for Allegheny County (Pittsburgh), Pennsylvania. METHODS: We used population-based statewide hospital discharge data, health system electronic medical record (EMR) data for RV tests, census data, and a published method to calculate burden. RESULTS: Among 26,211 eligible RV tests, 67.6% were negative for any virus. The viruses detected were rhinovirus/enterovirus (2552; 30.1%), influenza A (2,299; 27.1%), RSV (1082; 12.7%), human metapneumovirus (832; 9.8%), parainfluenza (601; 7.1%), influenza B (565; 6.7%), non-SARS-CoV-2 coronavirus (420; 4.9% 1.5 years of data available), and adenovirus (136; 1.6%). Most tests were among female (58%) and White (71%) patients with 60% of patients ≥65 years, 24% 50-64 years, and 16% 18-49 years. The annual burden ranged from 137-174/100,000 population for rhinovirus/enterovirus; 99-182/100,000 for influenza A; and 56-81/100,000 for RSV. Among adults <65 years, rhinovirus/enterovirus hospitalization burden was higher than influenza A; whereas the reverse was true for adults ≥65 years. RV hospitalization burden increased with increasing age. CONCLUSIONS: These virus-specific ARI population-based hospital burden estimates showed significant non-influenza burden. These estimates can serve as the basis for several areas of research that are essential for setting funding priorities and guiding public health policy.

Preterm birth among pregnant persons with severe acute respiratory syndrome Coronavirus 2 infection.

OBJECTIVE: We examined the relationship between trimester of SARS-CoV-2 infection, illness severity, and risk for preterm birth. STUDY DESIGN: We analyzed data for 6336 pregnant persons with SARS-CoV-2 infection in 2020 in the United States. Risk ratios for preterm birth were calculated for illness severity, trimester of infection, and illness severity stratified by trimester of infection adjusted for age, selected underlying medical conditions, and pregnancy complications. RESULT: Pregnant persons with critical COVID-19 or asymptomatic infection, compared to mild COVID-19, in the second or third trimester were at increased risk of preterm birth. Pregnant persons with moderate-to-severe COVID-19 did not show increased risk of preterm birth in any trimester. CONCLUSION: Critical COVID-19 in the second or third trimester was associated with increased risk of preterm birth. This finding can be used to guide prevention strategies, including vaccination, and inform clinical practices for pregnant persons.

The Effects of a Recent Major Hurricane on a Reproductive Medicine Clinic

Natural disasters and major weather events can have a large impact on fertility treatment in the affected area through unplanned clinic closures leading to cancelled cycles, severe weather endangering cryopreserved embryos and gametes, and long delays in the resumption of care related to infrastructure damage. The cessation of fertility treatment in these circumstances can lead to increased stress, anxiety, and trauma for patients and staff. As major weather events are expected to increase as a result of our warming planet, both the immediate effects of unplanned clinic closures and the long-term impacts on the success of assisted reproductive technology (ART) and pregnancy outcomes call for a closer evaluation of the effects of these events on the field of reproductive medicine. Research on developing new strategies to mitigate potential negative effects and improving our disaster preparedness is needed.

Correction: Structural Racism and Supporting Black Lives - A Pharmacist's Vow amid COVID-19.

[This corrects the article DOI: 10.24926/iip.v12i2.3411.].

Vaccine Equity: Lessons Learned from the COVID-19 Pandemic.

The COVID-19 pandemic has disproportionately affected racial and ethnic minorities, a group who is also less likely to be fully vaccinated. Vaccine hesitancy and vaccine access both play a role in the vaccine inequities observed during the COVID-19 pandemic. Strategies to improve access and reduce hesitancy are discussed.

Clearing the Fog: A Systematic Review on Cognitive Dysfunction in COVID-19 (preprint)

Objective: The systematic review aims to examine the association between COVID-19 and cognitive dysfunction, including the link between the severity of COVID-19 and the occurrence of cognitive impairment and the potential pathophysiological mechanisms related to brain fog among COVID-19 patients. Methods: PubMed, Oxford University Press, ProQuest Health and Medical Complete, ScienceDirect, Ovid, HERDIN, Google Scholar, and Cochrane Library databases were accessed to retrieve literature using the PRISMA guidelines. Results: After critical appraisal, thirteen full journal articles were included in the study. The studies showed the most frequent cognitive impairment are attention, memory, and executive function in COVID-19 patients. Compared with healthy controls (HC) in 3 out of 4 studies, cognitive impairment was only evident in COVID-19 patients. Furthermore, two studies showed no correlation between brain fog and depression, and five studies showed a link between the severity of COVID-19 infection and cognitive impairment. Cases ranging from mild to severe illness presented manifestations of brain fog. However, a disparity in the evidence of the pathophysiology of COVID-19 and cognitive dysfunction exists, prompting the need to investigate further. Additionally, recent studies provide insufficient evidence for direct central nervous system invasion, and there are emerging studies that contrast the presumed pathogenesis of neurological complications from neuroinflammation. Conclusion: There is an association between COVID-19 and cognitive dysfunction. Manifestation of cognitive dysfunction is present regardless of illness severity. Moreover, there are existing pathophysiological mechanisms of the Coronavirus that lead to cognitive dysfunction in COVID-19 patients; however, additional studies are required to substantiate such mechanisms further.

Induction of SARS-CoV-2 neutralizing antibodies by CoronaVac and BNT162b2 vaccines in naïve and previously infected individuals.

BACKGROUND: A major challenge of the SARS-CoV-2 pandemic is to better define "protective thresholds" to guide the global response. We aimed to characterize the longitudinal dynamics of the antibody responses in naturally infected individuals in Chile and compared them to humoral responses induced after immunization with CoronaVac-based on an inactivated whole virus -or the BNT162b2- based on mRNA-vaccines. We also contrasted them with the respective effectiveness and efficacy data available for both vaccines. METHODS: We determined and compared the longitudinal neutralizing (nAb) and anti-nucleocapsid (anti-N) antibody responses of 74 COVID-19 individuals (37 outpatient and 37 hospitalized) during the acute disease and convalescence. We also assessed the antibody boosting of 36 of these individuals who were immunized after convalescence with either the CoronaVac (n = 30) or the BNT162b2 (n = 6) vaccines. Antibody titres were also measured for 50 naïve individuals immunized with two doses of CoronaVac (n = 35) or BNT162b2 (n = 15) vaccines. The neutralizing level after vaccination was compared to those of convalescent individuals and the predicted efficacy was estimated. FINDINGS: SARS-CoV-2 infection induced robust nAb and anti-N antibody responses lasting >9 months, but showing a rapid nAb decay. After convalescence, nAb titres were significantly boosted by vaccination with CoronaVac or BNT162b2. In naïve individuals, the calculated mean titre induced by two doses of CoronaVac or BNT162b2 was 0·2 times and 5.2 times, respectively, that of convalescent individuals, which has been proposed as threshold of protection. CoronaVac induced no or only modest anti-N antibody responses. Using two proposed logistic models, the predicted efficacy of BNT162b2 was estimated at 97%, in close agreement with phase 3 efficacy studies, while for CoronaVac it was ∼50% corresponding to the lowest range of clinical trials and below the real-life data from Chile (from February 2 through May 1, 2021 during the predominant circulation of the Gamma variant), where the estimated vaccine effectiveness to prevent COVID-19 was 62·8-64·6%. INTERPRETATION: The decay of nAbs titres in previously infected individuals over time indicates that vaccination is needed to boost humoral memory responses. Immunization of naïve individuals with two doses of CoronaVac induced nAbs titres that were significantly lower to that of convalescent patients, and similar to vaccination with one dose of BTN162b2. The real life effectiveness for CoronaVac in Chile was higher than estimated; indicating that lower titres and additional cellular immune responses induced by CoronaVac might afford protection in a highly immunized population. Nevertheless, the lower nAb titre induced by two doses of CoronaVac as compared to the BTN162b2 vaccine in naïve individuals, highlights the need of booster immunizations over time to maintain protective levels of antibody, particularly with the emergence of new SARS-CoV-2 variants. FUNDING: FONDECYT 1161971, 1212023, 1181799, FONDECYT Postdoctorado 3190706 and 3190648, ANID Becas/Doctorado Nacional 21212258, PIA ACT 1408, CONICYT REDES180170, Centro Ciencia & Vida, FB210008, Financiamiento Basal para Centros Científicos y Tecnológicos de Excelencia grants from the Agencia Nacional de Investigación y Desarrollo (ANID) of Chile; NIH-NIAD grants U19AI135972, R01AI132633 and contracts HHSN272201400008C and 75N93019C00051; the JPB Foundation, the Open Philanthropy Project grant 2020-215611 (5384); and by anonymous donors. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Pregnancy and Infant Outcomes by Trimester of SARS-CoV-2 Infection in Pregnancy – SET-NET, 22 Jurisdictions, January 25, 2020 - December 31, 2020 (preprint)

Background: People with SARS-CoV-2 infection during pregnancy are at increased risk for adverse pregnancy outcomes, such as preterm birth and stillbirth. Few studies have assessed whether the risk of adverse pregnancy and infant outcomes varies by trimester of infection.Objectives: We describe clinical characteristics (i.e., treatment among pregnant people with moderate to critical illness) and pregnancy and infant outcomes in pregnant people with laboratory-confirmed SARS-CoV-2 infection by trimester of infection.Study Design: The Surveillance for Emerging Threats to Mothers and Babies Network (SET-NET) collects longitudinal data on people with confirmed SARS-CoV-2 infection during pregnancy and their infants. This analysis included people reported to SET-NET with infection in 2020, with known timing of infection and pregnancy outcome. Outcomes are described by trimester of infection. Pregnancy outcomes examined were live birth and pregnancy loss (<20 weeks gestation and ≥20 weeks gestation). Infant outcomes included preterm birth (<37 weeks gestation), small for gestational age (SGA), birth defects, and neonatal intensive care unit (NICU) admission. Adjusted prevalence ratios (aPR) were calculated for pregnancy and selected infant outcomes by trimester of infection, controlling for age, race/ethnicity and health insurance. Among those with moderate-to-critical COVID-19 illness, demographic and clinical characteristics of pregnant people by COVID-19 specific treatment status were described.Results: Among 44,914 people with SARS-CoV-2 infection in pregnancy, 35,200 (78.3%) people with known timing of infection and pregnancy outcome were included. There were 35,574 liveborn infants and 193 pregnancy losses (<20 weeks (n=52) and ≥20 weeks (n=141)) reported. Half (50.8%) of pregnant people had infection in the third trimester, 30.8% in the second, and 18.3% in the first. Third trimester infection was associated with a higher frequency of preterm birth compared to first or second trimester infection combined (17.8% vs. 11.8%; aPR 1.44 95% CI: 1.35-1.54). For term infants, those born to people with third trimester infection were more likely to be admitted to the NICU compared to those born to people with first or second trimester infections (6.7% vs. 4.5%, aPR 1.29, 95% CI: 1.16-1.36). Approximately five percent of infants were born SGA, with a higher frequency among infants born to people with third trimester infection (aPR 1.16, 95% CI: 1.06-1.27). Prevalence of birth defects was 553.4/10,000 live births, with no difference by trimester of infection. Of 1,732 pregnant people with moderate-to-critical illness, 24.4% (422 cases) were reported to have received any treatment, with 15.3% (265) receiving COVID-19 specific treatment. The most common COVID-19 treatments were remdesivir (57.0%), dexamethasone (45.8%), and azithromycin with hydroxychloroquine (15.4%).Conclusions: There were no signals for increased birth defects or SGA among infants in this population relative to national baseline estimates, regardless of timing of infection. However, the prevalence of preterm birth in people with SARS-CoV-2 infection in pregnancy in our analysis was higher relative to national baseline data (10.0-10.2%), particularly among people with third trimester infection. Consequences of COVID-19 during pregnancy, including preterm birth, support recommended COVID-19 prevention strategies, including vaccination for people who are pregnant or may become pregnant. The findings in this report further highlight gaps in COVID-19 treatment for pregnant people.

Antibody Responses In Non-Severe SARS-CoV-2 Infections Are Driven By CD4+ T cells and Age. (preprint)

SARS-CoV-2 infection causes a spectrum of clinical outcomes and diverse memory responses. Population studies indicate that viral neutralizing antibody responses are protective, but do not always develop post-infection. Other antiviral antibody effector functions, T-cell responses, or immunity to seasonal coronaviruses (OC43, 229E) have been implicated but not defined in all ages. Here, we identify that children and adult subjects generate polyfunctional antibodies to the spike protein after asymptomatic infection or mild disease, with some subjects developing cellular responses without seroconversion. Diversity in immunity was explained by two clusters distinguished by CD4+ T-cell cytokines, age, and antibodies to seasonal coronaviruses. Post-vaccination neutralizing responses were predicted by specific post-infection immune measures, including IL-2, spike-IgA, OC43-IgG1, 229E-IgM. We confirm a key role for CD4+ T cell cytokines in functionality of anti-spike antibodies, and show that antibody diversity is impacted by age, Th/Th2 cytokine biases, and antibody isotypes to SARS-CoV-2 and seasonal coronaviruses.