BACKGROUND AND OBJECTIVES: In 2023, the Advisory Committee on Immunization Practices recommended either Abrysvo, a vaccine administered during pregnancy, or nirsevimab, a monoclonal antibody administered to infants after birth, to protect infants from respiratory syncytial virus (RSV). Our objective was to assess the proportion of infants immunized against RSV through antenatal RSV vaccination or receipt of nirsevimab among linked pregnancy-infant dyads. METHODS: Using data from 10 Vaccine Safety Datalink health systems and a validated algorithm, we identified pregnant women aged 12 to 55 years with a live birth of 32 weeks' gestation or more from September 22, 2023, through March 31, 2024. We identified RSV vaccination using electronic health records supplemented with immunization information system (registry) data. Among infants from eligible pregnancies, we identified nirsevimab administered through March 31, 2024. We assessed infant RSV immunization, defined as exposure to antenatal RSV vaccination or receipt of nirsevimab, stratified by race and ethnicity, age, and birth month. RESULTS: A total of 36 949 eligible infants were included from 43 722 pregnancies. Overall, 72% of infants were immunized against RSV; estimates were highest among infants born to non-Hispanic (NH) Asian mothers (84%). Disparities were identified by race, with 60% coverage among infants born to NH Black or NH Middle Eastern or North African mothers. Coverage was 59% to 78% by birth month, with nirsevimab more commonly administered to infants born earlier in the season. CONCLUSIONS: In this population of infants, 72% were immunized against RSV. Although overall coverage was high, disparities in immunization by race and ethnicity are a call to action.

INTRODUCTION: Pandemic influenza vaccine development focuses on the hemagglutinin (HA) antigen for potency and immunogenicity. Antibody responses targeting the neuraminidase (NA) antigen, or the HA stalk domain have been implicated in protection against influenza. Responses to the NA and HA-stalk domain following pandemic inactivated influenza are not well characterized in humans. MATERIAL AND METHODS: In a series of clinical trials, we determine the vaccines' NA content and demonstrate that NA inhibition (NAI) antibody responses increase in a dose-dependent manner following a 2-dose priming series with AS03-adjuvanted influenza A(H7N9) inactivated vaccine (A(H7N9) IIV). NAI antibody responses also increase with interval extension of the 2-dose priming series or following a 5-year delayed boost with a heterologous adjuvanted A(H7N9) IIV. Neither concomitant seasonal influenza vaccination given simultaneously or sequentially, nor use of heterologous A(H7N9) IIVs in the 2-dose priming series had an appreciable effect on NAI antibody responses. Anti-HA stalk antibody responses were minimal and not durable. CONCLUSIONS: We provide evidence for strategies to improve anti-neuraminidase responses which can be further standardized for pandemic preparedness. CLINICAL TRIAL REGISTRY NUMBERS: NCT03312231, NCT03318315, NCT03589807, NCT03738241.

BACKGROUND: The JYNNEOS vaccine (two doses given 28 days apart) was recommended in the United States for people at high risk of exposure to monkeypox virus during the 2022 mpox outbreak. Our objective was to assess the safety of JYNNEOS using two complementary epidemiologic methods. METHODS: This observational cohort included patients of eight large integrated healthcare organizations who received JYNNEOS. Adverse events were identified using ICD-10 coded diagnoses assigned to medical visits. The first analysis used standardized incidence ratios (SIR) to compare the observed incidence of ten prespecified adverse events of special interest (AESI) during the 28 days after receipt of each dose of JYNNEOS to the expected incidence adjusted for several risk factors. The second analysis used tree-based data mining to identify temporal clustering of cases for more than 60,000 diagnoses and diagnosis groups within 70-days after JYNNEOS dose 1 administration. RESULTS: The SIR analysis included 53,583 adults who received JYNNEOS dose 1 and 38,206 who received dose 2. Males received 92% of the doses. There were no statistically significant elevated SIRs for any of the ten AESI. The tree-based data mining analysis included 36,912 vaccinees. Analysis of diagnoses in inpatient, emergency department, and outpatient settings identified statistically significant clusters of visits for rash and unspecified adverse effects. CONCLUSIONS: No new or unexpected safety concerns were identified. AESI did not occur more frequently than expected by chance alone. Non-serious medically attended adverse events, such as rash, have been previously reported and occurred infrequently.

IMPORTANCE: COVID-19 vaccination is recommended throughout pregnancy to prevent pregnancy complications and adverse birth outcomes associated with COVID-19 disease. To date, data on birth defects after first-trimester vaccination are limited. OBJECTIVE: To evaluate the associated risks for selected major structural birth defects among live-born infants after first-trimester receipt of a messenger RNA (mRNA) COVID-19 vaccine. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective cohort study of singleton pregnancies with estimated last menstrual period (LMP) between September 13, 2020, and April 3, 2021, and ending in live birth from March 5, 2021, to January 25, 2022. Included were data from 8 health systems in California, Oregon, Washington, Colorado, Minnesota, and Wisconsin in the Vaccine Safety Datalink. EXPOSURES: Receipt of 1 or 2 mRNA COVID-19 vaccine doses in the first trimester, as part of the primary series. MAIN OUTCOMES AND MEASURES: Selected major structural birth defects among live-born infants, identified from electronic health data using validated algorithms, with neural tube defects confirmed via medical record review. RESULTS: Among 42 156 eligible pregnancies (mean [SD] maternal age, 30.9 [5.0] years) 7632 (18.1%) received an mRNA COVID-19 vaccine in the first trimester. Of 34 524 pregnancies without a first-trimester COVID-19 vaccination, 2045 (5.9%) were vaccinated before pregnancy, 13 494 (39.1%) during the second or third trimester, and 18 985 (55.0%) were unvaccinated before or during pregnancy. Compared with pregnant people unvaccinated in the first trimester, those vaccinated in the first trimester were older (mean [SD] age, 32.3 [4.5] years vs 30.6 [5.1] years) and differed by LMP date. After applying stabilized inverse probability weighting, differences in baseline characteristics between vaccinated and unvaccinated pregnant persons in the first trimester were negligible (standardized mean difference <0.20). Selected major structural birth defects occurred in 113 infants (1.48%) after first-trimester mRNA COVID-19 vaccination and in 488 infants (1.41%) without first-trimester vaccine exposure; the adjusted prevalence ratio was 1.02 (95% CI, 0.78-1.33). In secondary analyses, with major structural birth defect outcomes grouped by organ system, no significant differences between infants vaccinated or unvaccinated in the first trimester were identified. CONCLUSIONS AND RELEVANCE: In this multisite cohort study, among live-born infants, first-trimester mRNA COVID-19 vaccine exposure was not associated with an increased risk for selected major structural birth defects.

IMPORTANCE: People with HIV (PWH) may be at increased risk for severe outcomes with COVID-19 illness compared with people without HIV. Little is known about COVID-19 vaccination coverage and factors associated with primary series completion among PWH. OBJECTIVES: To evaluate COVID-19 vaccination coverage among PWH and examine sociodemographic, clinical, and community-level factors associated with completion of the primary series and an additional primary dose. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study used electronic health record data to assess COVID-19 vaccination information from December 14, 2020, through April 30, 2022, from 8 health care organizations of the Vaccine Safety Datalink project in the US. Participants were adults diagnosed with HIV on or before December 14, 2020, enrolled in a participating site. MAIN OUTCOMES AND MEASURES: The percentage of PWH with at least 1 dose of COVID-19 vaccine and PWH who completed the COVID-19 vaccine primary series by December 31, 2021, and an additional primary dose by April 30, 2022. Rate ratios (RR) and 95% CIs were estimated using Poisson regression models for factors associated with completing the COVID-19 vaccine primary series and receiving an additional primary dose. RESULTS: Among 22 058 adult PWH (mean [SD] age, 52.1 [13.3] years; 88.8% male), 90.5% completed the primary series by December 31, 2021. Among 18 374 eligible PWH who completed the primary series by August 12, 2021, 15 982 (87.0%) received an additional primary dose, and 4318 (23.5%) received a booster dose by April 30, 2022. Receipt of influenza vaccines in the last 2 years was associated with completion of the primary series (RR, 1.17; 95% CI, 1.15-1.20) and an additional primary dose (RR, 1.61; 95% CI, 1.54-1.69). PWH with uncontrolled viremia (HIV viral load ≥200 copies/mL) (eg, RR, 0.90 [95% CI, 0.85-0.95] for viral load 200-10 000 copies/mL vs undetected or <200 copies/mL for completing the primary series) and Medicaid insurance (eg, RR, 0.89 [95% CI, 0.87-0.90] for completing the primary series) were less likely to be fully vaccinated. By contrast, greater outpatient utilization (eg, RR, 1.07 [95% CI, 1.05-1.09] for ≥7 vs 0 visits for primary series completion) and residence in counties with higher COVID-19 vaccine coverage (eg, RR, 1.06 [95% CI, 1.03-1.08] for fourth vs first quartiles for primary series completion) were associated with primary series and additional dose completion (RRs ranging from 1.01 to 1.21). CONCLUSIONS AND RELEVANCE: Findings from this cohort study suggest that, while COVID-19 vaccination coverage was high among PWH, outreach efforts should focus on those who did not complete vaccine series and those who have uncontrolled viremia.

During the COVID-19 pandemic, candidate COVID-19 vaccines were being developed for potential use in the United States on an unprecedented, accelerated schedule. It was anticipated that once available, under U.S. Food and Drug Administration (FDA) Emergency Use Authorization (EUA) or FDA approval, COVID-19 vaccines would be broadly used and potentially administered to millions of individuals in a short period of time. Intensive monitoring in the post-EUA/licensure period would be necessary for timely detection and assessment of potential safety concerns. To address this, the Centers for Disease Control and Prevention (CDC) convened an Advisory Committee on Immunization Practices (ACIP) work group focused solely on COVID-19 vaccine safety, consisting of independent vaccine safety experts and representatives from federal agencies - the ACIP COVID-19 Vaccine Safety Technical Work Group (VaST). This report provides an overview of the organization and activities of VaST, summarizes data reviewed as part of the comprehensive effort to monitor vaccine safety during the COVID-19 pandemic, and highlights selected actions taken by CDC, ACIP, and FDA in response to accumulating post-authorization safety data. VaST convened regular meetings over the course of 29 months, from November 2020 through April 2023; through March 2023 FDA issued EUAs for six COVID-19 vaccines from four different manufacturers and subsequently licensed two of these COVID-19 vaccines. The independent vaccine safety experts collaborated with federal agencies to ensure timely assessment of vaccine safety data during this time. VaST worked closely with the ACIP COVID-19 Vaccines Work Group; that work group used safety data and VaST's assessments for benefit-risk assessments and guidance for COVID-19 vaccination policy. Safety topics reviewed by VaST included those identified in safety monitoring systems and other topics of scientific or public interest. VaST provided guidance to CDC's COVID-19 vaccine safety monitoring efforts, provided a forum for review of data from several U.S. government vaccine safety systems, and assured that a diverse group of scientists and clinicians, external to the federal government, promptly reviewed vaccine safety data. In the event of a future pandemic or other biological public health emergency, the VaST model could be used to strengthen vaccine safety monitoring, enhance public confidence, and increase transparency through incorporation of independent, non-government safety experts into the monitoring process, and through strong collaboration among federal and other partners.

BACKGROUND: In the United States, annual vaccination against seasonal influenza is recommended for all people ages ≥ 6 months. Vaccination coverage assessments can identify populations less protected from influenza morbidity and mortality and help to tailor vaccination efforts. Within the Vaccine Safety Datalink population ages ≥ 6 months, we report influenza vaccination coverage for the 2017-18 through 2022-23 seasons. METHODS: Across eight health systems, we identified influenza vaccines administered from August 1 through March 31 for each season using electronic health records linked to immunization registries. Crude vaccination coverage was described for each season, overall and by self-reported sex; age group; self-reported race and ethnicity; and number of separate categories of diagnoses associated with increased risk of severe illness and complications from influenza (hereafter referred to as high-risk conditions). High-risk conditions were assessed using ICD-10-CM diagnosis codes assigned in the year preceding each influenza season. RESULTS: Among individual cohorts of more than 12 million individuals each season, overall influenza vaccination coverage increased from 41.9 % in the 2017-18 season to a peak of 46.2 % in 2019-20, prior to declaration of the COVID-19 pandemic. Coverage declined over the next three seasons, coincident with widespread SARS-CoV-2 circulation, to a low of 40.3 % in the 2022-23 season. In each of the six seasons, coverage was lowest among males, 18-49-year-olds, non-Hispanic Black people, and those with no high-risk conditions. While decreases in coverage were present in all age groups, the declines were most substantial among children: 2022-23 season coverage for children ages six months through 8 years and 9-17 years was 24.5 % and 22.4 % (14 and 10 absolute percentage points), respectively, less than peak coverage achieved in the 2019-20 season. CONCLUSIONS: Crude influenza vaccination coverage increased from 2017 to 18 through 2019-20, then decreased to the lowest level in the 2022-23 season. In this insured population, we identified persistent disparities in influenza vaccination coverage by sex, age, and race and ethnicity. The overall low coverage, disparities in coverage, and recent decreases in coverage are significant public health concerns.

There are limited data on influenza vaccination coverage among pregnant people in the United States during the coronavirus disease 2019 (COVID-19) pandemic. Within the Vaccine Safety Datalink, we conducted a retrospective cohort study to examine influenza vaccination coverage during the 2016-2017 through the 2021-2022 influenza seasons among pregnant people aged 18-49 years. Using influenza vaccines administered through March each season, we assessed crude coverage by demographic and clinical characteristics. Annual influenza vaccination coverage increased from the 2016-2017 season (63.0%) to a high of 71.0% in the 2019-2020 season. After the start of the COVID-19 pandemic, it decreased to a low of 56.4% (2021-2022). In each of the six seasons, coverage was lowest among pregnant people aged 18-24 years and among non-Hispanic Black pregnant people. The 2021-2022 season had the lowest coverage across all age and race and ethnicity groups. The recent decreases highlight the need for continued efforts to improve coverage among pregnant people.

The U.S. Food and Drug Administration authorized use of mRNA COVID-19 bivalent booster vaccines on August 31, 2022. Currently, CDC's clinical guidance states that COVID-19 and other vaccines may be administered simultaneously. At time of authorization and recommendations, limited data existed describing simultaneous administration of COVID-19 bivalent booster and other vaccines. We describe simultaneous influenza and mRNA COVID-19 bivalent booster vaccine administration between August 31-December 31, 2022, among persons aged ≥6 months in the Vaccine Safety Datalink (VSD) by COVID-19 bivalent booster vaccine type, influenza vaccine type, age group, sex, and race and ethnicity. Of 2,301,876 persons who received a COVID-19 bivalent booster vaccine, 737,992 (32.1%) received simultaneous influenza vaccine, majority were female (53.1%), aged ≥18 years (91.4%), and non-Hispanic White (55.7%). These findings can inform future VSD studies on simultaneous influenza and COVID-19 bivalent booster vaccine safety and coverage, which may have implications for immunization service delivery.

PURPOSE: Vaccine-associated enhanced disease (VAED) is a theoretical concern with new vaccines, although trials of authorized vaccines against SARS-CoV-2 have not identified markers for VAED. The purpose of this study was to detect any signals for VAED among adults vaccinated against coronavirus disease 2019 (COVID-19). METHODS: In this cross-sectional study, we assessed COVID-19 severity as a proxy for VAED among 400 adults hospitalized for COVID-19 from March through October 2021 at eight US healthcare systems. Primary outcomes were admission to an intensive care unit (ICU) and severe illness (score ≥6 on the World Health Organization [WHO] Clinical Progression Scale). We compared the risk of outcomes among those who had completed a COVID-19 vaccine primary series versus those who were unvaccinated. We incorporated inverse propensity weights for vaccination status in a doubly robust regression model to estimate the causal average treatment effect. RESULTS: The causal risk ratio in vaccinated versus unvaccinated was 0.36 (95% confidence interval [CI], 0.15-0.94) for ICU admission and 0.46 (95% CI, 0.25-0.76) for severe illness. CONCLUSION: Among hospitalized patients, reduced disease severity in those vaccinated against COVID-19 supports the absence of VAED.

Evaluations of vaccine effectiveness (VE) are important to monitor as COVID-19 vaccines are introduced in the general population. Research staff enrolled symptomatic participants seeking outpatient medical care for COVID-19-like illness or SARS-CoV-2 testing from a multisite network. VE was evaluated using the test-negative design. Among 236 SARS-CoV-2 nucleic acid amplification test-positive and 576 test-negative participants aged ≥16 years, VE of mRNA vaccines against COVID-19 was 91% (95% CI: 83-95) for full vaccination and 75% (95% CI: 55-87) for partial vaccination. Vaccination was associated with prevention of most COVID-19 cases among people seeking outpatient medical care.Competing Interest StatementMPN reports grants from Merck &amp; Co. outside the submitted work. RKZ reports grants from Sanofi Pasteur outside the submitted work. GKB reports grants from Merck &amp; Co outside the submitted work and consulting fees from New World Medical, LLC. ETM reports grants from Merck &amp; Co. outside the submitted work and consulting fees from Pfizer. ASM reports consulting fees from Sanofi Pasteur and Seqirus. LEL reports grants from Xcenda, Inc., eMAXHealth, AstraZeneca, Pfizer, Evidera outside the submitted work. MLJ reports grants from Sanofi Pasteur. All other authors report nothing to disclose.Funding StatementThis work was supported by the US Centers for Disease Control and Prevention through cooperative agreements U01IP001034-U01IP001039. At Pittsburgh, the project was also supported by the National Institutes of Health through grant ULTR001857.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Centers for Disease Control and Prevention IRB project determination numbers for included projects: 0900f3eb81c2e791, 0900f3eb81c52dc5; 0900f3eb81c52420, 0900f3eb81bc746b, 6238All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesDe-identified dataset can be made available upon request

We compared symptoms and characteristics of 4961 ambulatory patients with and without laboratory-confirmed SARS-CoV-2 infection. Findings indicate that clinical symptoms alone would be insufficient to distinguish between COVID-19 and other respiratory infections (e.g., influenza) and/or to evaluate the effects of preventive interventions (e.g., vaccinations).Competing Interest StatementAll authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: AM reports personal fees from Sanofi Pasteur and from Seqirus outside the submitted work; EB reports grants from CDC during the conduct of the study. EM reports grants from Centers for Disease Control and Prevention during the conduct of the study and personal fees from Pfizer outside the submitted work; LJ reports grants from CDC during the conduct of the study and grants from Novavax outside the submitted work; MG reports grants from Centers for Disease Control and Prevention during the conduct of the study and grants from Centers for Disease Control and Prevention - Abt Associates outside the submitted work; MJ reports grants from Centers for Disease Control during the conduct of the study and grants from Sanofi Pasteur outside the submitted work; MN reports grants from Centers for Disease Control and Prevention and National Institutes of Health during the conduct of the study and grants from Merck &amp; Co outside the submitted work; RZ reports grants from Centers for Disease Control and Prevention and National Institutes of Health during the conduct of the study and grants from Sanofi Pasteur outside the submitted work. All other authors have nothing to disclose.Funding StatementThis work was supported through cooperative agreements funded by US Centers for Disease Control and Prevention and, at the University of Pittsburgh, by infrastructure funding by UL1 TR001857 from National Institutes of Health.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Approved or waived by the Centers for Disease Control and Prevention (CDC) IRB with reliance on: 1.University of Michigan IRB (Approved) a. CDC protocol 6238 b. University of Michigan protocol HUM00119183 2. University of Pittsburgh IRB (Approved) a. CDC protocol 6219 b. University of Pittsburgh protocol STUDY19070407 3. Baylor Scott and White Health IRB (Approved) a. CDC protocols 7125 and 7277 b. Baylor Scott and White protocols 160145 and 20-153 4. Kaiser Permanente Washington Research Institute (Waived) 5. Marshfield Clinic Research Institute (Approved) a. CDC protocol 6197 b. Marshfield Clinic Research Institute protocol BEL10511 All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData may be made available in accordance with CDC data availability policy.

Individuals in contact with persons with COVID-19 are at high risk of developing COVID-19, but protection offered by COVID-19 vaccines in the context of known exposure is unknown. Symptomatic outpatients reporting acute onset of COVID-19-like illness and tested for SARSCoV-2 infection were enrolled. Among 2,229 participants, 283/451 (63%) of those reporting contact and 331/1778 (19%) without known contact tested SARS-CoV-2 positive. Using the test-negative design, adjusted vaccine effectiveness was 71% (95% confidence interval, 49%-83%) among fully vaccinated participants reporting contact versus 80% (95% CI, 72%-86%) among those without. This study supports COVID-19 vaccination and highlights the importance of efforts to increase vaccination coverage. Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license.

INTRODUCTION: Safety data on simultaneous vaccination (SV) with primary series monovalent COVID-19 vaccines and other vaccines are limited. We describe SV with primary series COVID-19 vaccines and assess 23 pre-specified health outcomes following SV among persons aged ≥5 years in the Vaccine Safety Datalink (VSD). METHODS: We utilized VSD's COVID-19 vaccine surveillance data from December 11, 2020-May 21, 2022. Analyses assessed frequency of SV. Rate ratios (RRs) were estimated by Poisson regression when the number of outcomes was ≥5 across both doses, comparing outcome rates between COVID-19 vaccinees receiving SV and COVID-19 vaccinees receiving no SV in the 1-21 days following COVID-19 vaccine dose 1 and 1-42 days following dose 2 by SV type received ("All SV", "Influenza SV", "Non-influenza SV"). RESULTS: SV with COVID-19 vaccines was not common practice (dose 1: 0.7 % of 8,455,037 persons, dose 2: 0.3 % of 7,787,013 persons). The most frequent simultaneous vaccines were influenza, HPV, Tdap, and meningococcal. Outcomes following SV with COVID-19 vaccines were rare (total of 56 outcomes observed after dose 1 and dose 2). Overall rate of outcomes among COVID-19 vaccinees who received SV was not statistically significantly different than the rate among those who did not receive SV (6.5 vs. 6.8 per 10,000 persons). Statistically significant elevated RRs were observed for appendicitis (2.09; 95 % CI, 1.06-4.13) and convulsions/seizures (2.78; 95 % CI, 1.10-7.06) in the "All SV" group following dose 1, and for Bell's palsy (2.82; 95 % CI, 1.14-6.97) in the "Influenza SV" group following dose 2. CONCLUSION: Combined pre-specified health outcomes observed among persons who received SV with COVID-19 vaccine were rare and not statistically significantly different compared to persons who did not receive SV with COVID-19 vaccine. Statistically significant adjusted rate ratios were observed for some individual outcomes, but the number of outcomes was small and there was no adjustment for multiple testing.

Background: Measles, mumps, and rubella vaccine (MMR) is routinely administered to children; however, adolescents and adults may receive MMR for various reasons. Safety studies in adolescents and adults are limited. We report on safety of MMR in this age group in the Vaccine Safety Datalink. Methods: We included adolescents (aged 9–17 years) and adults (aged ≥ 18 years) who received ≥ 1 dose of MMR from January 1, 2010–December 31, 2018. Pre-specified outcomes were identified by diagnosis codes. Clinically serious outcomes included anaphylaxis, encephalitis/myelitis, Guillain-Barré syndrome, immune thrombocytopenia, meningitis, and seizure. Non-serious outcomes were allergic reaction, arthropathy, fever, injection site reaction, lymphadenopathy, non-specific reaction, parotitis, rash, and syncope. All serious outcomes underwent medical record review. Outcome-specific incidence was calculated in pre-defined post-vaccination windows. A self-controlled risk interval design was used to determine the relative risk of each outcome in a risk window after vaccination compared to a more distal control window. Results: During the study period, 276,327 MMR doses were administered to adolescents and adults. Mean age of vaccinees was 34.8 years; 65.8 % were female; 53.2 % of doses were administered simultaneously with ≥ 1 other vaccine. Serious outcomes were rare, with incidence ≤ 6 per 100,000 doses for each outcome assessed, and none had a significant elevation in incidence during the risk window compared to the control window. Incidence of non-serious outcomes per 100,000 doses ranged from 3.4 for parotitis to 263.0 for arthropathy. Other common outcomes included injection site reaction and rash (157.0 and 112.9 per 100,000 doses, respectively). Significantly more outcomes were observed during the risk window compared to the control window for all non-serious outcomes except parotitis. Some variability was observed by sex and age group. Conclusion: Serious outcomes after MMR are rare in adolescents and adults, but vaccinees should be counseled regarding anticipated local and systemic non-serious adverse events. © 2023 The Author(s)

BACKGROUND: Epidemics of seasonal influenza vary in intensity annually, and influenza vaccine effectiveness (VE) fluctuates based in part on antigenic match to circulating viruses. We estimated the incidence of influenza and influenza cases averted by vaccination in four ambulatory care sites in the United States, during seasons when overall influenza VE ranged from 29% to 40%. METHODS: We conducted active surveillance for influenza at ambulatory care settings at four sites within the United States Influenza Vaccine Effectiveness Network. We extrapolated the total number of influenza cases in the source populations served by these organizations based on incidence of medically attended acute respiratory illness in the source population and influenza test results in those actively tested for influenza. We estimated the number of medically attended influenza cases averted based on incidence, vaccine coverage, and VE. RESULTS: From 2016/17 through 2018/19, incidence of ambulatory visits for laboratory-confirmed influenza ranged from 31 to 51 per 1,000 population. Incidence was highest in children aged 9-17years (range, 56 to 81 per 1,000) and lowest in adults aged 18-49years (range, 23-32 per 1,000). Medically attended cases averted by vaccination ranged from a high of 46.6 (95% CI, 12.1- 91.9) per 1,000 vaccinees in children aged 6months to 8years, to a low of 6.9 (95% CI, -5.1- 27.3) per 1,000 vaccinees in adults aged65years. DISCUSSION: Even in seasons with low vaccine effectiveness for a particular virus subtype, influenza vaccines can still lead to clinically meaningful reductions in ambulatory care visits for influenza.

Recombinant zoster vaccine (RZV) (Shingrix; GlaxoSmithKline, Brentford, United Kingdom) is an adjuvanted glycoprotein vaccine that was licensed in 2017 to prevent herpes zoster and its complications in older adults. In this prospective, post-licensure Vaccine Safety Datalink (VSD) study using electronic health records, we sequentially monitored a real-world population of adults aged 50 years and older who received care at multiple VSD health systems in the United States to identify potential increased risks of 10 pre-specified priority outcomes, including stroke, anaphylaxis, and Guillain-Barr Syndrome (GBS). Among 647,833 RZV doses administered from January 2018 through December 2019, we did not detect a sustained increased risk of any monitored outcome for RZV recipients relative either to historical (2013-2017) recipients of Zoster Vaccine Live (ZVL), a live-attenuated virus vaccine (Zostavax; Merck & Co., Inc., Kenilworth, New Jersey), or contemporary non-RZV vaccinated persons who had an annual well-visit during the 2018-2019 study period. We confirmed pre-licensure trial findings of increased risks of systemic and local reactions following RZV. Our study provides additional reassurance about the overall safety of RZV. Despite a large sample, uncertainty remains regarding potential associations with GBS due to the limited number of confirmed GBS cases that were observed.

BACKGROUND: Studying the safety of travel vaccines poses challenges since recipients may be traveling during the risk window for adverse events and the identification of a suitable comparison group can also be difficult. The examination of traveler characteristics, travel vaccination patterns, and health care utilization using electronic health record (EHR) data can inform the feasibility of future travel vaccine safety studies. METHODS: A retrospective cohort study of health plan members in the Vaccine Safety Datalink Project aged 9 months and older who had a travel-related encounter or received a travel vaccine from 2009 to 2018 was performed. Travel regions visited, travel duration, type of travel vaccine received (typhoid, yellow fever, Japanese encephalitis, rabies, and cholera), and timing of vaccination date before departure date were described. Sociodemographic information, clinical characteristics, and health care utilization were compared between travelers who received travel vaccines and travelers who did not. RESULTS: A total of 1,026,822 unique travelers departing from the United States were identified; 612,795 travelers received 898,196 doses of travel vaccines. The most commonly administered travel vaccine was typhoid vaccine and 77% of all travel vaccines were given more than one week prior to departure. Compared with travelers without travel vaccines, travelers with travel vaccines were overall similar but as a group were slightly younger, healthier, and had lower Hispanic representation. Health care utilization dramatically decreased during travel. Outpatient visits decreased from 294.8 visits per 10,000 person-days before travel to 24.2 visits per 10,000 person-days during reported travel dates. CONCLUSIONS: Through the EHR information from almost a million travelers, a departure date and duration of travel were successfully captured for the majority of travelers with corresponding health care utilization data. Time after vaccination and prior to departure can potentially be used in the future to compare travelers who receive travel vaccines with travelers who do not receive travel vaccines when looking at adverse events of interest after vaccination.

Biological response modifiers (BRM), also known as immunomodulators or cytokine inhibitors, are immunosuppressive substances that are increasingly being used to treat various autoimmune diseases,1 including during pregnancy. Some BRM are actively transported across the placenta barrier and can remain in infants for up to 12 months after birth,2,3 raising concerns that infants exposed to BRM in utero may be at increased risk of infections and adverse events after immunization with live attenuated vaccines.

Influenza vaccines can mitigate illness severity, including reduced risk of ICU admission and death, in people with breakthrough infection. Less is known about vaccine attenuation of mild/moderate influenza illness. We compared subjective severity scores in vaccinated and unvaccinated persons with medically attended illness and laboratory-confirmed influenza. Participants were prospectively recruited when presenting for care at five US sites over nine seasons. Participants aged ≥ 16 years completed the EQ-5D-5L visual analog scale (VAS) at enrollment. After controlling for potential confounders in a multivariable model, including age and general health status, VAS scores were significantly higher among 2,830 vaccinated participants compared with 3,459 unvaccinated participants, indicating vaccinated participants felt better at the time of presentation for care. No differences in VAS scores were observed by the type of vaccine received among persons aged ≥ 65 years. Our findings suggest vaccine-associated attenuation of milder influenza illness is possible.

OBJECTIVES: To determine whether children aged 4-7 years with a diagnosis of autism spectrum disorders (ASD) were at increased risk of fever, febrile seizures, or emergency department (ED) visits following measles- or pertussis-containing vaccines compared with children without ASD. METHODS: The study included children born between 1995-2012, aged 4-7 years at vaccination, and members of six healthcare delivery systems within Vaccine Safety Datalink. We conducted self-controlled risk interval analyses comparing rates of outcomes in risk and control intervals within each group defined by ASD status, and then compared outcome rates between children with and without ASD, in risk and control intervals, by estimating difference-in-differences using logistic regressions. RESULTS: The study included 14,947 children with ASD and 1,650,041 children without ASD. After measles- or pertussis-containing vaccination, there were no differences in association between children with and without ASD for fever (ratio of rate ratio for measles-containing vaccine = 1.07, 95% CI 0.58-1.96; for pertussis-containing vaccine = 1.16, 95% CI 0.63-2.15) or ED visits (ratio of rate ratio for measles-containing vaccine = 1.11, 95% CI 0.80-1.54; for pertussis-containing vaccine = 0.87, 95% CI 0.59-1.28). Febrile seizures were rare. Pertussis-containing vaccines were associated with small increased risk of febrile seizures in children without ASD. CONCLUSION: Children with ASD were not at increased risk for fever or ED visits compared with children without ASD following measles- or pertussis-containing vaccines. These results may provide further reassurance that these vaccines are safe for all children, including those with ASD.

BACKGROUND: Individuals in contact with persons with COVID-19 are at high risk of developing COVID-19; protection offered by COVID-19 vaccines in the context of known exposure is poorly understood. METHODS: Symptomatic outpatients aged ≥12 years reporting acute onset of COVID-19-like illness and tested for SARS-CoV-2 between February 1 and September 30, 2021 were enrolled. Participants were stratified by self-report of having known contact with a COVID-19 case in the 14 days prior to illness onset. Vaccine effectiveness was evaluated using the test-negative study design and multivariable logistic regression. RESULTS: Among 2229 participants, 283/451 (63%) of those reporting contact and 331/1778 (19%) without known contact tested SARS-CoV-2-positive. Adjusted vaccine effectiveness was 71% (95% confidence interval [CI], 49%-83%) among fully vaccinated participants reporting a known contact versus 80% (95% CI, 72%-86%) among those with no known contact (p-value for interaction = 0.2). CONCLUSIONS: This study contributes to growing evidence of the benefits of vaccinations in preventing COVID-19 and support vaccination recommendations and the importance of efforts to increase vaccination coverage.

BACKGROUND: Between May 2005 and March 2007, three vaccines were recommended by the Advisory Committee on Immunization Practices for routine use in adolescents in the United States: quadrivalent meningococcal conjugate vaccine (MenACWY), tetanus, diphtheria and acellular pertussis vaccine (Tdap), and human papillomavirus vaccine (HPV). Understanding historical adolescent vaccination patterns may inform future vaccination coverage efforts for these and emerging adolescent vaccines, including COVID-19 vaccines. METHODS: This was a descriptive, retrospective cohort study. All vaccines administered to adolescents aged 11 through 18years in the Vaccine Safety Datalink population between January 1, 2007 and December 31, 2016 were examined. Vaccination coverage was assessed by study year for 1 dose Tdap or Td, 1 dose Tdap, 1 dose MenACWY, 1 dose HPV, and 3 dose HPV. The proportion of vaccine visits with concurrent vaccination (2 vaccines administered at the same visit) was calculated by sex and study year. The most common vaccine combinations administered in the study population were described by sex for two time periods: 2007-2010 and 2011-2016. RESULTS: The number of 11-18-year-olds in the study population averaged 522,565 males and 503,112 females per study year. Between January 2007 and December 2016 there were 4,884,553 vaccine visits in this population (45% among males). The overall proportion of concurrent vaccine visits among males was 43% (33-61% by study year). Among females, 39% of all vaccine visits included concurrent vaccination (32-48% by study year). Vaccine coverage for Tdap, MenACWY, and 1- and 3-dose HPV increased across the study period. A wide variety of vaccine combinations were administered among both sexes and in both time periods. CONCLUSIONS: The high vaccine uptake and multitude of vaccine combinations administered concurrently in the adolescent population of the Vaccine Safety Datalink provide historical patterns with which to compare future adolescent vaccination campaigns.

COVID-19 vaccines are recommended during pregnancy to prevent severe maternal morbidity and adverse birth outcomes; however, vaccination coverage among pregnant women has been low (1). Concerns among pregnant women regarding vaccine safety are a persistent barrier to vaccine acceptance during pregnancy. Previous studies of maternal COVID-19 vaccination and birth outcomes have been limited by small sample size (2) or lack of an unvaccinated comparison group (3). In this retrospective cohort study of live births from eight Vaccine Safety Datalink (VSD) health care organizations, risks for preterm birth (<37 weeks' gestation) and small-for-gestational-age (SGA) at birth (birthweight <10th percentile for gestational age) after COVID-19 vaccination (receipt of ≥1 COVID-19 vaccine doses) during pregnancy were evaluated. Risks for preterm and SGA at birth among vaccinated and unvaccinated pregnant women were compared, accounting for time-dependent vaccine exposures and propensity to be vaccinated. Single-gestation pregnancies with estimated start or last menstrual period during May 17-October 24, 2020, were eligible for inclusion. Among 46,079 pregnant women with live births and gestational age available, 10,064 (21.8%) received ≥1 COVID-19 vaccine doses during pregnancy and during December 15, 2020-July 22, 2021; nearly all (9,892; 98.3%) were vaccinated during the second or third trimester. COVID-19 vaccination during pregnancy was not associated with preterm birth (adjusted hazard ratio [aHR] = 0.91; 95% CI = 0.82-1.01). Among 40,627 live births with birthweight available, COVID-19 vaccination in pregnancy was not associated with SGA at birth (aHR = 0.95; 95% CI = 0.87-1.03). Results consistently showed no increased risk when stratified by mRNA COVID-19 vaccine dose, or by second or third trimester vaccination, compared with risk among unvaccinated pregnant women. Because of the small number of first-trimester exposures, aHRs for first-trimester vaccination could not be calculated. These data add to the evidence supporting the safety of COVID-19 vaccination during pregnancy. To reduce the risk for severe COVID-19-associated illness, CDC recommends COVID-19 vaccination for women who are pregnant, recently pregnant (including those who are lactating), who are trying to become pregnant now, or who might become pregnant in the future (4).

OBJECTIVES: Safety studies assessing the association between the entire recommended childhood immunization schedule and autoimmune diseases, such as type 1 diabetes mellitus (T1DM), are lacking. To examine the association between the recommended immunization schedule and T1DM, we conducted a retrospective cohort study of children born between 2004 and 2014 in 8 US health care organizations that participate in the Vaccine Safety Datalink. METHODS: Three measures of the immunization schedule were assessed: average days undervaccinated (ADU), cumulative antigen exposure, and cumulative aluminum exposure. T1DM incidence was identified by International Classification of Disease codes. Cox proportional hazards models were used to analyze associations between the 3 exposure measures and T1DM incidence. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) were calculated. Models were adjusted for sex, race and ethnicity, birth year, mother's age, birth weight, gestational age, number of well-child visits, and study site. RESULTS: In a cohort of 584 171 children, the mean ADU was 38 days, the mean cumulative antigen exposure was 263 antigens (SD = 54), and the mean cumulative aluminum exposure was 4.11 mg (SD = 0.73). There were 1132 incident cases of T1DM. ADU (aHR = 1.01; 95% CI, 0.99-1.02) and cumulative antigen exposure (aHR = 0.98; 95% CI, 0.97-1.00) were not associated with T1DM. Cumulative aluminum exposure >3.00 mg was inversely associated with T1DM (aHR = 0.77; 95% CI, 0.60-0.99). CONCLUSIONS: The recommended schedule is not positively associated with the incidence of T1DM in children. These results support the safety of the recommended childhood immunization schedule.

Evaluations of vaccine effectiveness (VE) are important to monitor as COVID-19 vaccines are introduced in the general population. Research staff enrolled symptomatic participants seeking outpatient medical care for COVID-19-like illness or SARS-CoV-2 testing from a multisite network. VE was evaluated using the test-negative design. Among 236 SARS-CoV-2 nucleic acid amplification test-positive and 576 test-negative participants aged ≥16 years, VE of mRNA vaccines against COVID-19 was 91% (95% CI: 83-95) for full vaccination and 75% (95% CI: 55-87) for partial vaccination. Vaccination was associated with prevention of most COVID-19 cases among people seeking outpatient medical care.

Intra-season timing of influenza infection among persons of different ages could reflect relative contributions to propagation of seasonal epidemics and has not been examined among ambulatory patients. We calculated risk ratios derived from comparing weekly influenza cases pre-peak versus post-peak during the 2010-2011 through 2018-2019 influenza seasons using data from the US Influenza Vaccine Effectiveness network. We sought to determine age specific differences during the ascent versus the descent of a season by influenza virus types and subtypes. We estimated credible intervals around the risk ratios using Bayesian joint posterior sampling of weekly cases. Our population consisted of ambulatory patients with laboratory-confirmed influenza enrolled at five study sites during nine influenza seasons after the 2009 influenza A virus subtype H1N1 (H1N1) pandemic. We observed that young children aged <5 years tended to be more often infected with H1N1 during the pre-peak period while adults aged ≥65 years tended to be more often infected with H1N1 during the post-peak period. However, for influenza A virus subtype H3N2 children aged <5 years were more often infected during the post-peak period. These results may reflect a contribution of different age groups to seasonal spread, which may differ by influenza virus type and subtype.

Background: Identifying pregnancy episodes and accurately estimating their beginning and end dates are imperative for observational maternal vaccine safety studies using electronic health record (EHR) data. Methods: We modified the Vaccine Safety Datalink (VSD) Pregnancy Episode Algorithm (PEA) to include both the International Classification of Disease, ninth revision (ICD-9 system) and ICD-10 diagnosis codes, incorporated additional gestational age data, and validated this enhanced algorithm with manual medical record review. We also developed the new Dynamic Pregnancy Algorithm (DPA) to identify pregnancy episodes in real time. Results: Around 75% of the pregnancy episodes identified by the enhanced VSD PEA were live births, 12% were spontaneous abortions (SABs), 10% were induced abortions (IABs), and 0.4% were stillbirths (SBs). Gestational age was identified for 99% of live births, 89% of SBs, 69% of SABs, and 42% of IABs. Agreement between the PEA-assigned and abstractor-identified pregnancy outcome and outcome date was 100% for live births, but was lower for pregnancy losses. When gestational age was available in the medical record, the agreement was higher for live births (97%), but lower for pregnancy losses (75%). The DPA demonstrated strong concordance with the PEA and identified pregnancy episodes ⩾6 months prior to the outcome date for 89% of live births. Conclusion: The enhanced VSD PEA is a useful tool for identifying pregnancy episodes in EHR databases. The DPA improves the timeliness of pregnancy identification and can be used for near real-time maternal vaccine safety studies. Plain Language Summary: Improving identification of pregnancies in the Vaccine Safety Datalink electronic medical record databases to allow for better and faster monitoring of vaccination safety during pregnancy Introduction: It is important to monitor of the safety of vaccines after they have been approved and licensed by the Food and Drug Administration, especially among women vaccinated during pregnancy. The Vaccine Safety Datalink (VSD) monitors vaccine safety through observational studies within large databases of electronic medical records. Since 2012, VSD researchers have used an algorithm called the Pregnancy Episode Algorithm (PEA) to identify the medical records of women who have been pregnant. Researchers then use these medical records to study whether receiving a particular vaccine is linked to any negative outcomes for the woman or her child. Methods: The goal of this study was to update and enhance the PEA to include the full set of medical record diagnostic codes [both from the older International Classification of Disease, ninth revision (ICD-9 system) and the newer ICD-10 system] and to incorporate additional sources of data about gestational age. To ensure the validity of the PEA following these enhancements, we manually reviewed medical records and compared the results with the algorithm. We also developed a new algorithm, the Dynamic Pregnancy Algorithm (DPA), to identify women earlier in pregnancy, allowing us to conduct more timely vaccine safety assessments. Results: The new version of the PEA identified 2,485,410 pregnancies in the VSD database. The enhanced algorithm more precisely estimated the beginning of pregnancies, especially those that did not result in live births, due to the new sources of gestational age data. Conclusion: Our new algorithm, the DPA, was successful at identifying pregnancies earlier in gestation than the PEA. The enhanced PEA and the new DPA will allow us to better evaluate the safety of current and future vaccinations administered during or around the time of pregnancy. © The Author(s), 2021.

INTRODUCTION: Mid-season influenza vaccine effectiveness (VE) estimates are a useful tool to help guide annual influenza vaccine strain selection, vaccine policy, and public health messaging. We propose using a sample size-driven approach with data-driven inputs for publication of mid-season influenza VE. METHODS: We used pooled inputs for VE by (sub)type and average vaccine coverage by age groups using data from eight seasons of the US Influenza VE Network to calculate sample sizes needed to estimate mid-season VE. RESULTS: We estimate that 135 influenza-positive cases would be needed to detect an overall VE of 40% with 55% vaccine coverage among test-negative controls. Larger sample sizes would be required to produce reliable estimates specifically against influenza A/H3N2 and for older age groups. CONCLUSION: Using an existing network, most of the recent influenza seasons in the US would facilitate valid mid-season VE estimates using the proposed sample sizes for broad age groupings.

BACKGROUND: Recent studies have reported an increase in Inflammatory bowel disease (IBD) incidence in young children, highlighting the need to better understand risk factors for the development of IBD. Licensed for use in infants in 2006, the oral, live-attenuated rotavirus vaccine has biologic plausibility for instigating inflammation of the gut mucosa as a pathway to immune dysregulation. METHODS: Over a ten-year period, we evaluated incidence of IBD within a cohort of children under the age of ten, enrolled in seven integrated healthcare delivery systems. We conducted a nested case-control study to evaluate the association between rotavirus vaccination and IBD using conditional logistic regression. Cases were confirmed via medical record review and matched to non-IBD controls on date of birth, sex, and study site. RESULTS: Among 2.4 million children under the age of 10 years, 333 cases of IBD were identified with onset between 2007 and 2016. The crude incidence of IBD increased slightly over the study period (p-value for trend = 0.046). Of the 333 cases, 227 (68%) were born prior to 2007. Forty-two cases born in 2007 or later, with continuous enrollment since birth were included in the case-control study and matched to 210 controls. The adjusted odds ratio for any rotavirus vaccination in IBD cases, compared to matched controls, was 0.72 (95% confidence interval 0.19-2.65). CONCLUSIONS: Data from this large pediatric cohort demonstrate a small overall increase in IBD incidence in young children over a ten-year period. The data suggest that rotavirus vaccination is not associated with development of IBD.