Estimated population-level impact of pneumococcal conjugate vaccines against all-cause pneumonia mortality among unvaccinated age groups in five Latin American countries.

BACKGROUND: Pneumococcal conjugate vaccines (PCVs) provide strong direct protection in children, while limited data are available on their indirect effect on mortality among older age groups. This multi-country study aimed to assess the population-level impact of pediatric PCVs on all-cause pneumonia mortality among ≥5 years of age, and invasive pneumococcal disease (IPD) cases in Chile. METHODS: Demographic and mortality data from Argentina, Brazil, Chile, Colombia, and Mexico were collected considering the ≥ 5-year-old population, from 2000-2019, with 1,795,789 deaths due to all-cause pneumonia. IPD cases in Chile were also evaluated. Time series models were employed to evaluate changes in all-cause pneumonia deaths during the post-vaccination period, with other causes of death used as synthetic controls for unrelated temporal trends. RESULTS: No significant change in death rates due to all-cause pneumonia was detected following PCV introduction among most age groups and countries. The proportion of IPD cases caused by vaccine serotypes decreased from 29% (2012) to 6% (2022) among ≥65 years in Chile. DISCUSSION: While an effect of PCV against pneumonia deaths (a broad clinical definition that may not be specific enough to measure indirect effects) was not detected, evidence of indirect PCV impact was observed among vaccine-type-specific IPD cases.

Investigation of Sources of Fluorinated Compounds in Private Water Supplies in an Oil and Gas-Producing Region of Northern West Virginia.

Per- and polyfluoroalkyl substances (PFASs) are a class of toxic organic compounds that have been widely used in consumer applications and industrial activities, including oil and gas production. We measured PFAS concentrations in 45 private wells and 8 surface water sources in the oil and gas-producing Doddridge, Marshall, Ritchie, Tyler, and Wetzel Counties of northern West Virginia and investigated relationships between potential PFAS sources and drinking water receptors. All surface water samples and 60% of the water wells sampled contained quantifiable levels of at least one targeted PFAS compound, and four wells (8%) had concentrations above the proposed maximum contaminant level (MCL) for perfluorooctanoic acid (PFOA). Individual concentrations of PFOA and perfluorobutanesulfonic acid exceeded those measured in finished public water supplies. Total targeted PFAS concentrations ranged from nondetect to 36.8 ng/L, with surface water concentrations averaging 4-fold greater than groundwater. Semiquantitative, nontargeted analysis showed concentrations of emergent PFAS that were potentially higher than targeted PFAS. Results from a multivariate latent variable hierarchical Bayesian model were combined with insights from analyses of groundwater chemistry, topographic characteristics, and proximity to potential PFAS point sources to elucidate predictors of PFAS concentrations in private wells. Model results reveal (i) an increased vulnerability to contamination in upland recharge zones, (ii) geochemical controls on PFAS transport likely driven by adsorption, and (iii) possible influence from nearby point sources.

Incorporating data from multiple endpoints in the analysis of clinical trials: example from RSV vaccines.

Background: To achieve licensure, interventions typically must demonstrate efficacy against a primary outcome in a randomized clinical trial. However, selecting a single primary outcome a priori is challenging. Incorporating data from multiple and related outcomes might help to increase statistical power in clinical trials. Inspired by real-world clinical trials of interventions against respiratory syncytial virus (RSV), we examined methods for analyzing data on multiple endpoints. Method: We simulated data from three different populations in which the efficacy of the intervention and the correlation among outcomes varied. We developed a novel permutation-based approach that represents a weighted average of individual outcome test statistics ( varP ) to evaluate intervention efficacy in a multiple endpoint analysis. We compared the power and type I error rate of this approach to two alternative methods: the Bonferroni correction ( bonfT ) and another permutation-based approach that uses the minimum P-value across all test statistics ( minP ). Results: When the vaccine efficacy against different outcomes was similar, VarP yielded higher power than bonfT and minP; in some scenarios the improvement in power was substantial. In settings where vaccine efficacy was notably larger against one endpoint compared to the others, all three methods had similar power. Conclusions: Analyzing multiple endpoints using a weighted permutation method can increase power while controlling the type I error rate in settings where outcomes share similar characteristics, like RSV outcomes. We developed an R package, PERMEATE , to guide selection of the most appropriate method for analyzing multiple endpoints in clinical trials.

Waning Effectiveness of the BNT162b2 Vaccine Against Infection in Adolescents in Israel.

BACKGROUND: The short-term effectiveness of a 2-dose regimen of the BioNTech/Pfizer BNT162b2 vaccine for adolescents has been demonstrated. However, little is known about the long-term effectiveness in this age group. It is known, however, that waning of vaccine-induced immunity against infection in adult populations is evident within a few months. METHODS: Leveraging the database of Maccabi Healthcare Services (MHS), we conducted a matched case-control design for evaluating the association between time since vaccination and the incidence of infections, where 2 outcomes were evaluated: documented SARS-CoV-2 infection (regardless of symptoms) and symptomatic infection (COVID-19). Cases were defined as individuals aged 12-16 with a positive polymerase chain reaction (PCR) test occurring between 15 June and 8 December 2021, when the Delta variant was dominant in Israel. Controls were adolescents who had not tested positive previously. RESULTS: We estimated a peak vaccine effectiveness between 2 weeks and 3 months following receipt of the second dose, with 85% (95% confidence interval [CI]: 84-86%) and 90% (95% CI: 89-91%) effectiveness against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19), respectively. However, in line with findings for adults, waning effectiveness was evident. Long-term protection was reduced to 73% (95% CI: 68-77%) against infection and 79% (95% CI: 73-83%) against COVID-19 3-5 months after the second dose and waned to 53% (95% CI: 46-60%) against infection and 66% (95% CI: 59-72%) against COVID-19 after 5 months. CONCLUSIONS: Although vaccine-induced protection against both infection and COVID-19 continues over time in adolescents, the protection wanes with time since vaccination, starting 3 months after inoculation and continuing for more than 5 months.

Vaccination with BNT162b2 reduces transmission of SARS-CoV-2 to household contacts in Israel.

The effectiveness of vaccines against COVID-19 on the individual level is well established. However, few studies have examined vaccine effectiveness against transmission. We used a chain binomial model to estimate the effectiveness of vaccination with BNT162b2 [Pfizer-BioNTech messenger RNA (mRNA)-based vaccine] against household transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Israel before and after emergence of the B.1.617.2 (Delta) variant. Vaccination reduced susceptibility to infection by 89.4% [95% confidence interval (CI): 88.7 to 90.0%], whereas vaccine effectiveness against infectiousness given infection was 23.0% (95% CI: -11.3 to 46.7%) during days 10 to 90 after the second dose, before 1 June 2021. Total vaccine effectiveness was 91.8% (95% CI: 88.1 to 94.3%). However, vaccine effectiveness is reduced over time as a result of the combined effect of waning of immunity and emergence of the Delta variant.

Waning Effectiveness of the BNT162b2 Vaccine Against Infection in Adolescents.

BACKGROUND: The short-term effectiveness of a two-dose regimen of the BioNTech/Pfizer mRNA BNT162b2 vaccine for adolescents has been demonstrated. However, little is known about the long-term effectiveness in this age group. It is known, though, that waning of vaccine-induced immunity against infection in adult populations is evident within a few months. METHODS: Leveraging the centralized computerized database of Maccabi Healthcare Services (MHS), we conducted a matched case-control design for evaluating the association between time since vaccination and the incidence of infections, where two outcomes were evaluated separately: a documented SARS-CoV-2 infection (regardless of symptoms) and a symptomatic infection (COVID-19). Cases were defined as individuals aged 12 to 16 with a positive PCR test occurring between June 15 and December 8, 2021, when the Delta variant was dominant in Israel. Controls were adolescents who had not tested positive previously. RESULTS: We estimated a peak vaccine effectiveness between 2 weeks and 3 months following receipt of the second dose, with 85% and 90% effectiveness against SARS-CoV-2 infection and COVID-19, respectively. However, in line with previous findings for adults, waning of vaccine effectiveness was evident in adolescents as well. Long-term protection conferred by the vaccine was reduced to 75-78% against infection and symptomatic infection, respectively, 3 to 5 months after the second dose, and waned to 58% against infection and 65% against COVID-19 after 5 months. CONCLUSIONS: Like adults, vaccine-induced protection against both SARS-CoV-2 infection and COVID-19 wanes with time, starting three months after inoculation and continuing for more than five months.

Odds of Testing Positive for SARS-CoV-2 Following Receipt of 3 vs 2 Doses of the BNT162b2 mRNA Vaccine.

Importance: With the evidence of waning immunity of the mRNA vaccine BNT162b2 (Pfizer-BioNTech), a nationwide third-dose (booster) vaccination campaign was initiated in Israel during August 2021; other countries have begun to administer a booster shot as well. Objective: To evaluate the initial short-term additional benefit of a 3-dose vs a 2-dose regimen against infection of SARS-CoV-2. Design, Setting, and Participants: This preliminary retrospective case-control study used 2 complementary approaches: a test-negative design and a matched case-control design. Participants were included from the national centralized database of Maccabi Healthcare Services, an Israeli healthcare maintenance organization covering 2.5 million members. Data were collected between March 1, 2020, and October 4, 2021, and analyses focused on the period from August 1, 2021, to October 4, 2021, because the booster dose was widely administered from August 1 onward. Exposures: Either 2 doses or 3 doses of the BNT162b2 vaccine. Main Outcomes and Measures: The reduction in the odds of a positive SARS-CoV-2 polymerase chain reaction (PCR) test at different time intervals following receipt of the booster dose (0-6, 7-13, 14-20, 21-27, and 28-65 days) compared with receiving only 2 doses. Results: The study population included 306 710 members of Maccabi Healthcare Services who were 40 years and older (55% female) and received either 2 or 3 doses of the BNT162b2 vaccine and did not have a positive PCR test result for SARS-CoV-2 prior to the start of the follow-up period. During this period, there were 500 232 PCR tests performed, 227 380 among those who received 2 doses and 272 852 among those who received 3 doses, with 14 989 (6.6%) and 4941 (1.8%) positive test results in each group, respectively. Comparing those who received a booster and those who received 2 doses, there was an estimated odds ratio of 0.14 (95% CI, 0.13-0.15) 28 to 65 days following receipt of the booster (86% reduction in the odds of testing positive for SARS-CoV-2). Conclusion and Relevance: Previous studies have demonstrated that vaccine-derived protection against SARS-CoV-2 wanes over time. In this case-control analysis, we showed an association between receipt of the booster dose and a reduction in the odds of testing positive for SARS-CoV-2, potentially counteracting waning immunity in the short term. Further monitoring of data from this population is needed to determine the duration of immunity following the booster.

Evaluating the Impact of Meningococcal Vaccines With Synthetic Controls.

Invasive meningococcal disease (IMD) has a low and unpredictable incidence, presenting challenges for real-world evaluations of meningococcal vaccines. Traditionally, meningococcal vaccine impact is evaluated by predicting counterfactuals from pre-immunization IMD incidences, possibly controlling for IMD in unvaccinated age groups, but the selection of controls can influence results. We retrospectively applied a synthetic control (SC) method, previously used for pneumococcal disease, to data from 2 programs for immunization of infants against serogroups B and C IMD in England and Brazil. Time series of infectious/noninfectious diseases in infants and IMD cases in older unvaccinated age groups were used as candidate controls, automatically combined in a SC through Bayesian variable selection. SC closely predicted IMD in absence of vaccination, adjusting for nontrivial changes in IMD incidence. Vaccine impact estimates were in line with previous assessments. IMD cases in unvaccinated age groups were the most frequent SC-selected controls. Similar results were obtained when excluding IMD from control sets and using other diseases only, particularly respiratory diseases and measles. Using non-IMD controls may be important where there are herd immunity effects. SC is a robust and flexible method that addresses uncertainty introduced when equally plausible controls exhibit different post-immunization behaviors, allowing objective comparisons of IMD programs between countries.

Vaccination with BNT162b2 reduces transmission of SARS-CoV-2 to household contacts in Israel.

The individual-level effectiveness of vaccines against clinical disease caused by SARS-CoV-2 is well-established. However, few studies have directly examined the effect of COVID-19 vaccines on transmission. We quantified the effectiveness of vaccination with BNT162b2 (Pfizer-BioNTech mRNA-based vaccine) against household transmission of SARS-CoV-2 in Israel. We fit two time-to-event models - a mechanistic transmission model and a regression model - to estimate vaccine effectiveness against susceptibility to infection and infectiousness given infection in household settings. Vaccine effectiveness against susceptibility to infection was 80-88%. For breakthrough infections among vaccinated individuals, the vaccine effectiveness against infectiousness was 41-79%. The overall vaccine effectiveness against transmission was 88.5%. Vaccination provides substantial protection against susceptibility to infection and slightly lower protection against infectiousness given infection, thereby reducing transmission of SARS-CoV-2 to household contacts. ONE-SENTENCE SUMMARY: Vaccination reduced both the rate of infection with SARS-CoV-2 and transmission to household contacts in Israel.