Importance: Evidence is needed to determine COVID-19 vaccine effectiveness under real world conditions of use. Objective: To determine the effectiveness of authorized vaccines against COVID-19 in the context of substantial circulation of SARS-CoV-2 variants of concern, and identify vaccine uptake barriers. Design: We recruited cases (testing positive) and controls (testing negative) based on SARS-CoV-2 molecular diagnostic test results from 24 February-7 April 2021. Controls were individually matched to cases by age, sex, and geographic region. We identified cases and controls via random sampling within predetermined demographic strata. We conducted enrollment and administered study questionnaires via telephone-based facilitated interviews. Setting: Population-based surveillance of all SARS-CoV-2 molecular diagnostic testing reported to the California Department of Public Health. During the study period, 69% of sequenced SARS-CoV-2 isolates in California belonged to variants of concern B.1.1.7, B.1.427, or B.1.429. Participants: We enrolled 645 adults aged ≥18y, including 325 cases and 320 controls Exposures: We assessed participants' self-reported history of COVID-19 vaccine receipt (BNT162b2 and mRNA-1273). Individuals were considered fully vaccinated two weeks after second dose receipt. Main Outcomes and Measures: The primary endpoint was a positive SARS-CoV-2 molecular test result. For unvaccinated participants, we assessed willingness to receive vaccination, when eligible. We measured vaccine effectiveness via the matched odds ratio of prior vaccination, comparing cases with controls. Results: Among 325 cases, 23 (7%) and 13 (4%) received BNT162b2 and mRNA-1273, respectively; 8 (2%) were fully vaccinated with either product. Among 260 controls, 49 (19%) and 49 (19%) received BNT162b2 and mRNA-1273, respectively; 42 (16%) were fully vaccinated with either product. Among fully vaccinated individuals, vaccine effectiveness was 86% (95% confidence interval: 67-94%). Vaccine effectiveness was 66% (-69% to 93%) and 78% (23% to 94%) one week following a first and second dose, respectively. Among unvaccinated participants, 39% of those residing in rural regions and 23% of those residing in urban regions reported hesitancy to receive COVID-19 vaccines, when eligible. In contrast, vaccine hesitancy did not significantly differ by age, sex, household income, or race/ethnicity. Conclusions and Relevance: Ongoing vaccination efforts are preventing SARS-CoV-2 infection in the general population in California. Vaccine hesitancy presents a barrier to reaching coverage levels needed for herd immunity.
The test-negative design has become the standard approach for assessing real-world performance of vaccines against influenza, with increasing applications in studies of other infectious disease interventions. Vaccine effectiveness is measured from the exposure odds ratio (OR) of vaccination among individuals seeking treatment for acute respiratory illness who receive a laboratory test for influenza infection. This approach is argued to provide a natural correction for differential healthcareseeking behavior among vaccinated and unvaccinated persons. However, the relation of the measured OR to true vaccine effectiveness is not well established. We derive the OR under circumstances consistent with real-world test-negative studies. The OR recovers the true vaccine direct effect when two circumstances are met: (1) that vaccination is uncorrelated with exposure or susceptibility to infection, and (2) that vaccination confers "all-or-nothing" protection (whereby certain individuals have no protection while others are perfectly protected). Biased effect size estimates, potentially including sign bias, arise if either condition is unmet. Such bias may generate time-varying OR estimates suggestive of vaccine waning in the absence of true time-varying protection. Troublingly, the test-negative design may fail to correct for differential healthcare-seeking behavior among vaccinated and unvaccinated persons unless stringent clinical criteria are upheld for enrollment and testing. Our findings demonstrate a need to reassess how data from test-negative studies are interpreted for policy decisions conventionally based on causal inferences.peer-reviewed)
Despite widespread vaccination, eleven thousand mumps cases were reported in the United States (US) in 2016-17, including hundreds in Massachusetts, primarily in college settings. We generated 203 whole genome mumps virus (MuV) sequences from Massachusetts and 15 other states to understand the dynamics of mumps spread locally and nationally, as well as to search for variants potentially related to vaccination. We observed multiple MuV lineages circulating within Massachusetts during 2016-17, evidence for multiple introductions of the virus to the state, and extensive geographic movement of MuV within the US on short time scales. We found no evidence that variants arising during this outbreak contributed to vaccine escape. Combining epidemiological and genomic data, we observed multiple co-circulating clades within individual universities as well as spillover into the local community. Detailed data from one well-sampled university allowed us to estimate an effective reproductive number within that university significantly greater than one. We also used publicly available small hydrophobic (SH) gene sequences to estimate migration between world regions and to place this outbreak in a global context, but demonstrate that these short sequences, historically used for MuV genotyping, are inadequate for tracing detailed transmission. Our findings suggest continuous, often undetected, circulation of mumps both locally and nationally, and highlight the value of combining genomic and epidemiological data to track viral disease transmission at high resolution.
Background: Reduced-dose pneumococcal conjugate vaccine (PCV) schedules are under consideration in countries where children are currently recommended to receive three PCV doses. However, dosespecific PCV effectiveness against vaccine-serotype colonization is uncertain.Methods: From 2009-2016, we conducted surveillance of pneumococcal carriage in southern Israel, where PCV is administered at ages 2, 4, and 12 months (2+1 schedule). We obtained nasopharyngeal swabs and vaccination histories from 4245 children ages 0-59 months without symptoms of diseases that could be caused by pneumococci. In a case-control analysis, we measured protection against vaccineserotype colonization as one minus the matched odds ratio for PCV doses received.Results: At ages 5-12 months, a second PCV7/13 dose increased protection against PCV7-serotype carriage from -23.6% (95%CI: -209.7-39.1%) to 27.1% (-69.2-64.5%), and a second PCV13 dose increased protection against carriage of all PCV13 serotypes from -54.8% (-404.3-39.1%) to 23.4% (-128.5-67.1%). At ages 13-24 months, a third PCV7/13 dose increased protection against PCV7-serotype carriage from 32.4% (-8.4-58.0%) to 74.1% (58.4-84.6%), and a third PCV13 dose increased protection against carriage of all PCV13 serotypes from -50.0% (-194.0-42.7%) to 49.7% (15.8-83.3%). On average, each PCV13 dose conferred 37.7% (7.0-61.8%) greater protection against carriage of serotypes 1, 5, 6A, 7F, and 19A than carriage of serotype 3. PCV13-derived protection against carriage of serotypes 1, 5, 6A, 7F, and 19A was equivalent to PCV7/13-derived protection against carriage of PCV7 serotypes. Conclusions:In a setting implementing a 2+1 PCV schedule, protection against vaccine-serotype colonization is sustained primarily by the third dose.
Background: Case-carrier ratios quantifying the relative pathogenicity of serotypes can inform vaccine formulations for antigenically-diverse pathogens. However, sparse serotype-specific counts in epidemiologic datasets may undermine such analyses, most notably for rare serotypes that pose emergence risks in vaccinated populations. This challenge is well-illustrated in Group B streptococcus (GBS), where serotype III dominates in both carriage and disease. Methods:We develop an empirical Bayes random-effects model based on conjugate Dirichletmultinomial distributions of serotype frequencies in carriage and disease states. We validate the model using simulated datasets, and apply it to data from 15 paired sets of GBS isolates from intrapartum rectovaginal colonization (n=3403) and neonatal invasive disease (NID; n=1088), 16 from blood (n=2352) and cerebrospinal fluid (n=780) neonatal specimens, and 3 from fatal (n=173) and non-fatal (n=1684) neonatal invasive infections. Results:Our method accurately recovers parameters in simulated datasets. Using this approach, we confirm that GBS serotype III exhibits the greatest invasiveness, followed by serotype Ia with a 75.3% (95%CrI: 43.7-93.8%) lower estimate. Enhanced invasiveness of serotypes III and Ia is most evident in late-onset disease. Non-hexavalent-vaccine serotypes, which are rare in carriage and disease, generally show lower invasiveness; serotype IX/non-typeable GBS, the most prevalent cause of non-vaccinepreventable disease, is 98.7% (81.7-99.9%) and 94.2% (13.9-99.6%) less invasive than serotypes III and Ia, respectively. Conclusions:We present a strategy for measuring associations of serotype with carrier and disease states in the presence of sparse counts, avoiding biases that exist in common ad-hoc approaches. METHODS Outcome definitionWe aimed to measure the association of serotype with the following epidemiologic features of neonatal invasive GBS:
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