SARS-CoV-2 Attack Rate and Population Immunity in Southern New England, March 2020 to May 2021.

Importance: In emergency epidemic and pandemic settings, public health agencies need to be able to measure the population-level attack rate, defined as the total percentage of the population infected thus far. During vaccination campaigns in such settings, public health agencies need to be able to assess how much the vaccination campaign is contributing to population immunity; specifically, the proportion of vaccines being administered to individuals who are already seropositive must be estimated. Objective: To estimate population-level immunity to SARS-CoV-2 through May 31, 2021, in Rhode Island, Massachusetts, and Connecticut. Design, Setting, and Participants: This observational case series assessed cases, hospitalizations, intensive care unit occupancy, ventilator occupancy, and deaths from March 1, 2020, to May 31, 2021, in Rhode Island, Massachusetts, and Connecticut. Data were analyzed from July 2021 to November 2021. Exposures: COVID-19-positive test result reported to state department of health. Main Outcomes and Measures: The main outcomes were statistical estimates, from a bayesian inference framework, of the percentage of individuals as of May 31, 2021, who were (1) previously infected and vaccinated, (2) previously uninfected and vaccinated, and (3) previously infected but not vaccinated. Results: At the state level, there were a total of 1 160 435 confirmed COVID-19 cases in Rhode Island, Massachusetts, and Connecticut. The median age among individuals with confirmed COVID-19 was 38 years. In autumn 2020, SARS-CoV-2 population immunity (equal to the attack rate at that point) in these states was less than 15%, setting the stage for a large epidemic wave during winter 2020 to 2021. Population immunity estimates for May 31, 2021, were 73.4% (95% credible interval [CrI], 72.9%-74.1%) for Rhode Island, 64.1% (95% CrI, 64.0%-64.4%) for Connecticut, and 66.3% (95% CrI, 65.9%-66.9%) for Massachusetts, indicating that more than 33% of residents in these states were fully susceptible to infection when the Delta variant began spreading in July 2021. Despite high vaccine coverage in these states, population immunity in summer 2021 was lower than planned owing to an estimated 34.1% (95% CrI, 32.9%-35.2%) of vaccines in Rhode Island, 24.6% (95% CrI, 24.3%-25.1%) of vaccines in Connecticut, and 27.6% (95% CrI, 26.8%-28.6%) of vaccines in Massachusetts being distributed to individuals who were already seropositive. Conclusions and Relevance: These findings suggest that future emergency-setting vaccination planning may have to prioritize high vaccine coverage over optimized vaccine distribution to ensure that sufficient levels of population immunity are reached during the course of an ongoing epidemic or pandemic.

SARS-CoV-2 epidemic after social and economic reopening in three U.S. states reveals shifts in age structure and clinical characteristics.

State-level reopenings in late spring 2020 facilitated the resurgence of severe acute respiratory syndrome coronavirus 2 transmission. Here, we analyze age-structured case, hospitalization, and death time series from three states-Rhode Island, Massachusetts, and Pennsylvania-that had successful reopenings in May 2020 without summer waves of infection. Using 11 daily data streams, we show that from spring to summer, the epidemic shifted from an older to a younger age profile and that elderly individuals were less able to reduce contacts during the lockdown period when compared to younger individuals. Clinical case management improved from spring to summer, resulting in fewer critical care admissions and lower infection fatality rate. Attack rate estimates through 31 August 2020 are 6.2% [95% credible interval (CI), 5.7 to 6.8%] of the total population infected for Rhode Island, 6.7% (95% CI, 5.4 to 7.6%) in Massachusetts, and 2.7% (95% CI, 2.5 to 3.1%) in Pennsylvania.

SARS-CoV-2 attack rate and population immunity in southern New England, March 2020 - May 2021.

Estimating an infectious disease attack rate requires inference on the number of reported symptomatic cases of a disease, the number of unreported symptomatic cases, and the number of asymptomatic infections. Population-level immunity can then be estimated as the attack rate plus the number of vaccine recipients who had not been previously infected; this requires an estimate of the fraction of vaccines that were distributed to seropositive individuals. To estimate attack rates and population immunity in southern New England, we fit a validated dynamic epidemiological model to case, clinical, and death data streams reported by Rhode Island, Massachusetts, and Connecticut for the first 15 months of the COVID-19 pandemic, from March 1 2020 to May 31 2021. This period includes the initial spring 2020 wave, the major winter wave of 2020-2021, and the lagging wave of lineage B.1.1.7(Alpha) infections during March-April 2021. In autumn 2020, SARS-CoV-2 population immunity (equal to the attack rate at that point) in southern New England was still below 15%, setting the stage for a large winter wave. After the roll-out of vaccines in early 2021, population immunity in many states was expected to approach 70% by spring 2021, with more than half of this immune population coming from vaccinations. Our population immunity estimates for May 31 2021 are 73.4% (95% CrI: 72.9% - 74.1%) for Rhode Island, 64.1% (95% CrI: 64.0% - 64.4%) for Connecticut, and 66.3% (95% CrI: 65.9% - 66.9%) for Massachusetts, indicating that >33% of southern Englanders were still susceptible to infection when the Delta variant began spreading in July 2021. Despite high vaccine coverage in these states, population immunity in summer 2021 was lower than planned due to 34% (Rhode Island), 25% (Connecticut), and 28% (Massachusetts) of vaccine distribution going to seropositive individuals. Future emergency-setting vaccination planning will likely have to consider over-vaccination as a strategy to ensure that high levels of population immunity are reached during the course of an ongoing epidemic.

SARS-CoV-2 epidemic after social and economic reopening in three US states reveals shifts in age structure and clinical characteristics.

In the United States, state-level re-openings in spring 2020 presented an opportunity for the resurgence of SARS-CoV-2 transmission. One important question during this time was whether human contact and mixing patterns could increase gradually without increasing viral transmission, the rationale being that new mixing patterns would likely be associated with improved distancing, masking, and hygiene practices. A second key question to follow during this time was whether clinical characteristics of the epidemic would improve after the initial surge of cases. Here, we analyze age-structured case, hospitalization, and death time series from three states - Rhode Island, Massachusetts, and Pennsylvania - that had successful re-openings in May 2020 without summer waves of infection. Using a Bayesian inference framework on eleven daily data streams and flexible daily population contact parameters, we show that population-average mixing rates dropped by >50% during the lockdown period in March/April, and that the correlation between overall population mobility and transmission-capable mobility was broken in May as these states partially re-opened. We estimate the reporting rates (fraction of symptomatic cases reporting to health system) at 96.0% (RI), 72.1% (MA), and 75.5% (PA); in Rhode Island, when accounting for cases caught through general-population screening programs, the reporting rate estimate is 94.5%. We show that elderly individuals were less able to reduce contacts during the lockdown period when compared to younger individuals. Attack rate estimates through August 31 2020 are 6.4% (95% CI: 5.8% ‒ 7.3%) of the total population infected for Rhode Island, 5.7% (95% CI: 5.0% ‒ 6.8%) in Massachusetts, and 3.7% (95% CI: 3.1% ‒ 4.5%) in Pennsylvania, with some validation available through published seroprevalence studies. Infection fatality rates (IFR) estimates for the spring epidemic are higher in our analysis (>2%) than previously reported values, likely resulting from the epidemics in these three states affecting the most vulnerable sub-populations, especially the most vulnerable of the ≥80 age group.

Peroxisome proliferator-activated receptor-gamma ligands induce heme oxygenase-1 in lung fibroblasts by a PPARgamma-independent, glutathione-dependent mechanism.

Oxidative stress plays an important role in the pathogenesis of pulmonary fibrosis. Heme oxygenase-1 (HO-1) is a key antioxidant enzyme, and overexpression of HO-1 significantly decreases lung inflammation and fibrosis in animal models. Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a transcription factor that regulates adipogenesis, insulin sensitization, and inflammation. We report here that the PPARgamma ligands 15d-PGJ2 and 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO), which have potent antifibrotic effects in vitro, also strongly induce HO-1 expression in primary human lung fibroblasts. Pharmacological and genetic approaches are used to demonstrate that induction of HO-1 is PPARgamma independent. Upregulation of HO-1 coincides with decreased intracellular glutathione (GSH) levels and can be inhibited by N-acetyl cysteine (NAC), a thiol antioxidant and GSH precursor. Upregulation of HO-1 is not inhibited by Trolox, a non-thiol antioxidant, and does not involve the transcription factors AP-1 or Nrf2. CDDO and 15d-PGJ2 contain an alpha/beta unsaturated ketone that acts as an electrophilic center that can form covalent bonds with free reduced thiols. Rosiglitazone, a PPARgamma ligand that lacks an electrophilic center, does not induce HO-1. These data suggest that in human lung fibroblasts, 15d-PGJ2 and CDDO induce HO-1 via a GSH-dependent mechanism involving the formation of covalent bonds between 15d-PGJ2 or CDDO and GSH. Inhibiting HO-1 upregulation with NAC has only a small effect on the antifibrotic properties of 15d-PGJ2 and CDDO in vitro. These results suggest that CDDO and similar electrophilic PPARgamma ligands may have great clinical potential as antifibrotic agents, not only through direct effects on fibroblast differentiation and function, but indirectly by bolstering antioxidant defenses.