December 1, 2022

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Clinical Reports

Is the risk of still and preterm birth affected by the timing of symptomatic SARS-CoV-2 infection during pregnancy?
Among 14,264 eligible participants from 70 countries who did not report a pregnancy loss before 20 gestational weeks, 5893 had completed their pregnancies and reported delivery information; others were censored at time of their last follow-up. Participants with symptomatic COVID-19 before 20 weeks’ gestation had no increased risk of preterm delivery compared to those testing negative, with adjusted risks of 10.0% (95% CI 7.8, 12.0) vs. 9.8% (9.1, 10.5). Mild COVID-19 later in pregnancy was not clearly associated with preterm delivery. In contrast, severe COVID-19 after 20 weeks’ gestation led to an increase in preterm delivery compared to milder disease. For example, the risk ratio for preterm delivery comparing severe to mild/moderate COVID-19 at 35 weeks was 2.8 (2.0, 4.0); corresponding risk ratios for indicated and spontaneous preterm delivery were 3.7 (2.0, 7.0) and 2.3 (1.2, 3.9), respectively. Severe COVID-19 late in pregnancy sharply increased the risk of preterm delivery compared to no COVID-19. This elevated risk was primarily due to an increase in medically indicated preterm deliveries, included preterm cesarean sections, although an increase in spontaneous preterm delivery was also observed. In contrast, mild or moderate COVID-19 conferred minimal risk, as did severe disease early in pregnancy.

Antiviral Therapeutics and Vaccines

Effectiveness of Influenza Vaccination of Pregnant Women for Prevention of Maternal and Early Infant Influenza-Associated Hospitalizations in South Africa
Influenza vaccination during pregnancy reduces influenza-associated illness in the women and their infants, but effectiveness estimates against influenza-associated hospitalization are limited and lacking from settings with high human immunodeficiency virus (HIV) infection prevalence. Researchers assessed the effect of maternal vaccination in HIV-uninfected women and women with HIV in preventing influenza-associated hospitalizations in infants and the women. During 2015–2018, influenza vaccination campaigns targeting pregnant women were augmented at selected antenatal clinics; these were coupled with prospective hospital-based surveillance for acute respiratory or febrile illness in infants aged <6 months and cardiorespiratory illness among pregnant or postpartum women. Vaccine effectiveness (VE) was assessed using a test-negative case-control study. Overall, 71 influenza-positive and 371 influenza-negative infants were included in the analysis; mothers of 26.8% of influenza-positive infants were vaccinated during pregnancy compared with 35.6% of influenza-negative infants, corresponding to an adjusted VE (aVE) of 29.0% (95% confidence interval [CI], −33.6% to 62.3%). When limited to vaccine-matched strains, aVE was 65.2% (95% CI, 11.7%–86.3%). For maternal hospitalizations, 56 influenza-positive and 345 influenza-negative women were included in the analysis, with 28.6% of influenza-positive women being vaccinated compared with 38.3% of influenza-negatives, for an aVE of 46.9% (95% CI, −2.8% to 72.5%). Analysis restricted to HIV-uninfected women resulted in 82.8% (95% CI, 40.7%–95.0%) aVE. No significant aVE (−32.5% [95% CI, −208.7% to 43.1%]) was detected among women with HIV. Influenza vaccination during pregnancy prevented influenza-associated hospitalizations among young infants when infected with vaccine strains and among HIV-uninfected women.
A multivalent nucleoside-modified mRNA vaccine against all known influenza virus subtypes
Seasonal influenza vaccines offer little protection against pandemic influenza virus strains. It is difficult to create effective prepandemic vaccines because it is uncertain which influenza virus subtype will cause the next pandemic. In this work, we developed a nucleoside-modified messenger RNA (mRNA)–lipid nanoparticle vaccine encoding hemagglutinin antigens from all 20 known influenza A virus subtypes and influenza B virus lineages. This multivalent vaccine elicited high levels of cross-reactive and subtype-specific antibodies in mice and ferrets that reacted to all 20 encoded antigens. Vaccination protected mice and ferrets challenged with matched and mismatched viral strains, and this protection was at least partially dependent on antibodies. Our studies indicate that mRNA vaccines can provide protection against antigenically variable viruses by simultaneously inducing antibodies against multiple antigens.
Single and 2-dose vaccinations with modified vaccinia Ankara-Bavarian Nordic® induce durable B cell memory responses comparable to replicating smallpox vaccines
Though Modified Vaccinia Ankara - Bavarian Nordic (MVA-BN®). vaccination is approved for smallpox and monkeypox prevention, immunological persistence and booster effects remain undescribed. Participants naïve to smallpox vaccination were randomized to 1 dose MVA-BN (1×MVA, N = 181), 2 doses MVA-BN (2×MVA, N = 183), or placebo (N = 181). Participants with previous smallpox vaccination received 1 MVA-BN booster (HSPX⁺, N = 200). Subsets of the formerly naïve groups (∼75 each) received an MVA-BN booster 2 years later. Neutralizing antibody (nAb) geometric mean titers (GMTs) increased from 1.1 (baseline, both naïve groups) to 7.2 and 7.5 (Week 4, 1×MVA and 2×MVA, respectively), and further to 45.6 (Week 6, 2×MVA after second vaccination). In HSPX⁺, nAb GMT rapidly increased from 21.6 (baseline) to 175.1 (Week 2). At 2 years, GMTs for 1×MVA, 2×MVA, and HSPX⁺were 1.1, 1.3, and 10.3, respectively. After boosting in the previously naïve groups, nAb GMTs increased rapidly in 2 weeks to 80.7 (1×MVA) and 125.3 (2×MVA), higher than after primary vaccination and comparable to boosted HSPX⁺ Six months after boosting, GMTs were 25.6 (1×MVA) and 49.3 (2×MVA). No safety concerns were identified. Anamnestic responses without sustained high nAb titers support presence of durable immunological memory following MVA-BN immunization.
Cross-neutralization of Omicron subvariants after heterologous NVX-CoV2373 boosters: Comparison between prior SARS-CoV-2-infected and infection-naive individuals
Both third- and fourth-dose heterologous NVX-CoV2373 boosters enhanced cross-reactive immunity against Omicron BA.1/BA.5 subvariants among infection-naive individuals. Although repeated vaccination at short intervals showed ceiling effect in prior-infected individuals, which was consistent with previous reports, prior SARS-CoV-2 infection may provide better cross-protection against diverse Omicron subvariants.
Alarming antibody evasion properties of rising SARS-CoV-2 BQ and XBB subvariants
The SARS-CoV-2 Omicron variant continues to evolve, with new BQ and XBB subvariants now rapidly expanding in Europe/US and Asia, respectively. As these new subvariants have additional spike mutations, they may possess altered antibody evasion properties. Here, researchers report that neutralization of BQ.1, BQ.1.1, XBB, and XBB.1 by sera from vaccines and infected persons was markedly impaired, including sera from individuals who were boosted with a WA1/BA.5 bivalent mRNA vaccine. Compared to the ancestral strain D614G, serum neutralizing titers against BQ and XBB subvariants were lower by 13-81-fold and 66-155-fold, respectively, far beyond what had been observed to date. A panel of monoclonal antibodies capable of neutralizing the original Omicron variant, including those with Emergency Use Authorization, were largely inactive against these new subvariants. The spike mutations that conferred antibody resistance were individually studied and structurally explained. Finally, the ACE2-binding affinities of the spike proteins of these novel subvariants were found to be similar to those of their predecessors. Taken together, these findings indicate that BQ and XBB subvariants present serious threats to the efficacy of current COVID-19 vaccines, render inactive all authorized monoclonal antibodies, and may have gained dominance in the population because of their advantage in evading antibodies.
Real-world evidence of novel treatments for COVID-19 on mortality: a nationwide comparative cohort study of hospitalized patients in the 1^st, 2^nd, 3^rdand 4^thwave in the Netherlands
Large clinical trials on drugs for hospitalized COVID-19 patients have shown significant effects on mortality. There may be a discrepancy with the observed real-world effect. Researchers describe the clinical characteristics and outcomes of hospitalized COVID-19 patients in the Netherlands during four pandemic waves, and analyze the association of the newly introduced treatments with mortality, ICU-admission, and discharge alive. Researchers conducted a nationwide retrospective analysis of hospitalized COVID-19 patients between 27 February 2020 and 31 December 2021. Patients were categorized into waves and into treatment groups (hydroxychloroquine, remdesivir, neutralizing SARS-CoV-2 mAb, corticosteroids, and IL-6 antagonists). Four types of Cox-regression analyses were used: unadjusted, adjusted, propensity matched, and propensity weighted. Among 5643 patients from 11 hospitals we observed a changing epidemiology during four pandemic waves, with a decrease in median age (67 to 64 years, p < 001), in in-hospital mortality on the ward (21% to 15%, p < 0.001), and a trend on the ICU (24% to 16%, p = 0.148). In ward patients, hydroxychloroquine was associated with increased mortality (1.54 (95% CI 1.22-1.96)); remdesivir with a higher rate of discharge alive within 29 days (1.16 (95% CI 1.03-1.31)). Corticosteroids were associated with a decrease in mortality (0.82 (95% CI 0.69-0.96); the results of IL-6 antagonists were inconclusive. In patients directly admitted to the ICU, hydroxychloroquine, corticosteroids, and IL-6 antagonists were not associated with decreased mortality. Both remdesivir and corticosteroids were associated with better outcomes in ward patients with COVID-19. Continuous evaluation of real-world treatment effects is needed.
Effectiveness and safety of extended thromboprophylaxis in post-discharge patients with COVID-19
In post-discharge patients with COVID-19 at high risk of thromboembolism, extended thromboprophylaxis, primarily prophylactic use of anticoagulants for <35 days, can significantly reduce the risk of thrombosis and all-cause mortality without increasing the risk of major bleeding events.

Epidemiology

Medical Masks Versus N95 Respirators for Preventing COVID-19 Among Health Care Workers: A Randomized Trial
Among health care workers who provided routine care to patients with COVID-19, the overall estimates rule out a doubling in hazard of RT-PCR–confirmed COVID-19 for medical masks when compared with HRs of RT-PCR–confirmed COVID-19 for N95 respirators. The subgroup results varied by country, and the overall estimates may not be applicable to individual countries because of treatment effect heterogeneity.