3-dose Primary Series Research Articles

362. Safety and Immunogenicity of a Variant-adapted Bivalent (Original/Omicron BA.4/BA.5) BNT162b2 COVID-19 Vaccine Given as a Booster (Dose 4) to Toddlers and Children 6 Months to < 5 Years of Age Who Previously Received Original BNT162b2 as a 3-Dose Primary Series

Abstract Background A variant-adapted bivalent BNT162b2 vaccine (bivalent BNT162b2) comprised of original SARS-CoV-2 and Omicron BA.4/BA.5 spike proteins was developed to improve protection against SARS-CoV-2 variants. Bivalent BNT162b2 is authorized by the US FDA from 6 months (mo) old; for children 6 mo to < 5 years (y), it is authorized as a 3-dose primary series and as a fourth dose (first booster). Methods This substudy is part of a phase 1/2/3 master study (NCT05543616) investigating safety and immunogenicity of bivalent BNT162b2. The group reported here is open label and evaluates a fourth dose (first booster) with bivalent BNT162b2 3 μg in children 6 mo to < 5 y who previously received 3 original BNT162b2 3 μg doses. Reactogenicity (7 day), and 1 mo safety and immunogenicity for a subset of 60 participants were assessed. Descriptive immunogenicity endpoints included SARS-CoV-2 Omicron BA.4/BA.5 and ancestral strain neutralization responses post dose 4. A comparator group for immunogenicity included 60 participants, matched by age and SARS-CoV-2 infection status, from the initial pediatric study (NCT04816643) who received 3 original BNT162b2 3 μg doses without a booster. Results Of children 6 mo to < 5 y old (6 mo to < 2 y, n = 24; 2 y to < 5 y, n = 36) who received bivalent BNT162b2 as a fourth dose, 50% were male, 58% White, 5% Black, 15% Asian, 22% multiracial, 25% Hispanic/Latino; 28.3% had evidence of past SARS-CoV-2 infection. Median time from dose 3 of original BNT162b2 to bivalent BNT162b2 was 6.5 mo. Bivalent BNT162b2 was generally well tolerated with mostly mild to moderate reactogenicity and minimal fever (Figure), few reported adverse events (AEs), no serious AEs, and no new safety signals identified. Bivalent BNT162b2 elicited higher neutralizing titers against Omicron BA.4/BA.5 and similar titers against ancestral strain 1 mo post dose 4 compared with original BNT162b2 1 mo post dose 3 (Table). Robust immune responses were observed regardless of previous SARS-CoV-2 infection status. Conclusion A booster (dose 4) of bivalent BNT162b2 had a similar safety profile to original BNT162b2 and induced robust Omicron BA.4/BA.5 and ancestral strain neutralizing titers in children 6 mo to < 5 y. These descriptive data reinforce the importance of a variant-adapted bivalent COVID-19 booster dose in this age group. Disclosures Lawrence Sher, MD, Pfizer Inc: Clinical Investigator Charu Sabharwal, MD, MPH, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Nicholas Kitchin, MD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Justice Kofi Boakya-Appiah, MD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Xia Xu, PhD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Emmanuel Walter, MD, Clinetic: Clinical Investigator|Iliad Biotechnologies: Advisor/Consultant|Moderna: Clinical Investigator|Najit Technologies: Clinical Investigator|Pfizer Inc: Clinical Investigator|Sequiris: Clinical Investigator|Vaxcyte: Advisor/Consultant Yvonne A. Maldonado, MD, Pfizer: Grant/Research Support|Pfizer: Site Investigator, DSMB member Flor M. Munoz, MD, MSc, CDC respiratory virus surveillance: Grant/Research Support|Gilead: Grant/Research Support|Moderna, sanofi, aztra zeneca, Merck, GSK: Advisor/Consultant|NIH: DSMB|NIH COVID-19 vaccines in pregnancy: Grant/Research Support|Pfizer Pediatric COVID-19 vaccines: Grant/Research Support|Pfizer, Dynavax, Monderna, Meissa, NIH: DSMB Janet A. Englund, MD, Ark Biopharma: Advisor/Consultant|AstraZeneca: Advisor/Consultant|AstraZeneca: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Meissa Vaccines: Advisor/Consultant|Merck: Grant/Research Support|Moderna: Advisor/Consultant|Moderna: Grant/Research Support|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Sanofi Pasteur: Advisor/Consultant Kawsar R. Talaat, MD, Intralytix: Advisor/Consultant|Merck: Advisor/Consultant|NIAID: DSMB|Pfizer: Grant/Research Support|Pfizer: Pfizer contract with institution|Sanofi: Grant/Research Support|Takeda: Advisor/Consultant Satoshi Kamidani, MD, CDC: Grant/Research Support|Emergent BioSolutions: Grant/Research Support|NIH: Grant/Research Support|Pfizer Inc: Grant/Research Support Grant C. Paulsen, MD, Moderna: Grant/Research Support|Pfizer: Grant/Research Support Lisa Moyer, BS, Pfizer: Employee|Pfizer: Stocks/Bonds Vrunda Parikh, PharmD, Pfizer: Employee|Pfizer: Stocks/Bonds Hua Ma, PhD, Pfizer: Employee|Pfizer: Stocks/Bonds Xingbin Wang, PhD, Pfizer: Employee|Pfizer: Stocks/Bonds Kenneth Koury, PhD, Pfizer: Employee|Pfizer: Stocks/Bonds Annaliesa S. Anderson, PhD, Pfizer: Employee|Pfizer: Stocks/Bonds Kena A. Swanson, Ph.D., Pfizer: Employee|Pfizer: Stocks/Bonds Alejandra C. Gurtman, M.D, Pfizer: Employee|Pfizer: Stocks/Bonds William C. Gruber, MD, Pfizer, Inc.: Employee|Pfizer, Inc.: Stocks/Bonds

Prevalence of prolonged otitis media with effusion among 2 to 3 years old Cameroonian children in the era of 13-valent pneumococcal conjugate vaccines

ObjectivesThere is data scarcity on the overall effects of pneumococcal conjugate vaccines (PCVs) on otitis media (OM) in low- and middle-income countries. The impact of the 13-valent PCV (PCV13) program on OM was evaluated in Cameroon where infant vaccination was implemented in July 2011 using a 3-dose primary series at 6, 10 and 14 weeks of age. MethodsThrough community-based surveillance, we used a retrospective cohort study design to assess OM prevalence among PCV13-vaccinated children aged 24 to 36 months in 2015. This was compared with a 2013 age-matched cohort of PCV13-unvaccinated children. OM was diagnosed by clinical inspection for chronic suppurative OM (CSOM) and tympanometry for OM with effusion (OME). CSOM was defined as draining of the middle ear with duration of more than 2 weeks and prolonged OME was defined as a flat ‘type B’ tympanogram. PCV13-vaccinated and PCV13-unvaccinated cohorts were compared by calculating prevalence odds ratios for OM and baseline characteristics. ResultsAltogether, 111 OM cases were identified; 42/433 (9.7%) in the PCV13-unvaccinated in 2013 and 69/413 (16.7%) in the PCV13-vaccinated cohort in 2015. In the 2013 baseline survey, 3/433 (0.7%) children were identified with unilateral CSOM compared to 9/413 (2.2%) in the PCV13-vaccinated cohort in 2015. Bilateral prolonged OME was diagnosed in 7/433 (1.6%) PCV13-unvaccinated children and in 12/413 (2.9%) in PCV13-vaccinated children. Proportions of children with unilateral prolonged OME were 31/433 (7.2%) in the PCV13-unvaccinated group compared with 48/413 (11.6%) in the PCV13-vaccinated group. Multivariate logistic regression analysis showed evidence that PCV13-vaccinated children in 2015 had 40% less risk of contracting OM compared to PCV13-unvaccinated children in 2013 (adjusted prevalence odds ratios = 0.60 [95% confidence interval: 0.38 to 0.94], P = 0.025). Additionally, attributable proportion estimates show that, 58% of OM infections among the PCV13-vaccinated group would still have occurred despite PCV13 vaccination. ConclusionOur findings provide significant evidence on the effect of PCV13 in decreasing OM or OME among children in this age group. It also supports justification for government's continuation of PCV13 immunization program in the absence of GAVI's funding. Further research is needed to assess the long-term impact of the PCV13 program on in OM Cameroon.

Risk Factors for Not Completing a 2-Dose Primary Series of Messenger RNA COVID-19 Vaccination in a Large Health Care System in Southern California: Retrospective Cohort Study.

COVID-19 vaccination is crucial in combating the COVID-19 pandemic. Messenger RNA COVID-19 vaccines were initially authorized as a 2-dose primary series and have been widely used in the United States; completing the 2-dose primary series offers protection against infection, severe illness, and death. Understanding the risk factors for not completing the 2-dose primary series is critical to evaluate COVID-19 vaccination programs and promote completion of the 2-dose primary series. This study examined potential risk factors for not completing a 2-dose primary series of mRNA COVID-19 vaccination. We conducted a retrospective cohort study among members aged ≥18 years from a large integrated health care system, Kaiser Permanente Southern California, from December 14, 2020, to June 30, 2022. Noncompletion of the 2-dose primary series was defined as not completing the second dose within 6 months after receipt of the first dose. Crude noncompletion rates were estimated overall and by demographic characteristics, health care use patterns, comorbidity, and community-level socioeconomic factors. A Poisson regression model was fit to examine associations of individual-level and community-level risk factors with noncompletion of the 2-dose primary series. Among 2.5 million recipients of ≥1 dose of mRNA COVID-19 vaccines, 3.3% (n=81,202) did not complete the second dose within 6 months. Members aged 25-44 years, 65-74 years, and ≥75 years were less likely to not complete the 2-dose primary series than those aged 18-24 years, while members aged 45-64 years were more likely to not complete the 2-dose primary series (adjusted risk ratio [aRR] 1.13, 95% CI 1.10-1.15). Male sex was associated with a higher risk of noncompletion (aRR 1.17, 95% CI 1.15-1.19). Hispanic and non-Hispanic Black race/ethnicity were associated with a lower risk of noncompletion (range aRR 0.78-0.91). Having Medicaid and prior influenza vaccination were associated with a higher risk of noncompletion. Having SARS-CoV-2 infection, experiencing an adverse event, or having an inpatient and emergency department visit during the minimum recommended dose intervals were associated with a higher risk of not completing the 2-dose primary series (aRR 1.98, 95% CI 1.85-2.12; 1.99, 95% CI 1.43-2.76; and 1.85, 95% CI 1.77-1.93, respectively). Those who received the first dose after June 30, 2021, were more likely to not complete the 2-dose primary series within 6 months of receipt of the first dose. Despite limitations such as being a single-site study and the inability to consider social factors such as employment and vaccine attitudes, our study identified several risk factors for not completing a 2-dose primary series of mRNA vaccination, including being male; having Medicaid coverage; and experiencing SARS-CoV-2 infection, adverse events, or inpatient and emergency department visits during the minimum recommended dose intervals. These findings can inform future efforts in developing effective strategies to enhance vaccination coverage and improve the completion rate of necessary doses.

Multisystem Inflammatory Syndrome in Children Among Persons Who Completed a Two-dose COVID-19 Vaccine Primary Series Compared With Those Reporting No COVID-19 Vaccination, US National MIS-C Surveillance.

We analyzed multisystem inflammatory syndrome in children cases by reported COVID-19 vaccination status (2-dose primary series vs. no vaccination). A total of 46% vaccinated versus 58% unvaccinated persons received intensive care unit-level care ( P = 0.02); the risk of intensive care unit admission was 23% higher (adjusted relative risk: 1.23; 95% confidence interval: 1.03-1.48) among unvaccinated patients; 21 unvaccinated persons died. Multisystem inflammatory syndrome in children occurs after SARS-CoV-2 infection in vaccinated persons, but may be less severe.

Pertussis in Mexico from 2000 to 2019: A real-world study of incidence, vaccination coverage, and vaccine effectiveness

BackgroundThe national immunization program in Mexico includes a 3-dose primary series of pertussis vaccine and a toddler booster dose. In Mexico, whole-cell pertussis vaccines (wP) were switched in 2007 to acellular pertussis vaccines (aP). MethodsThis retrospective study using Mexican National Databases of Health and population surveillance (2000–2019) assessed the incidence of pertussis, infant pertussis vaccination coverage, and vaccine effectiveness (VE) against clinically-diagnosed and/or laboratory-confirmed pertussis in children aged 6.5–18.5 or 24.5 months for the primary series, and children aged 18.5 or 24.5–48.5 months for the toddler booster. ResultsThe incidence of pertussis sharply increased in 2012 and was highest in 2012, 2015, and 2016 (0.84–0.94/100,000 person-years). Coverage was highest for the first dose in the primary series, decreasing for each subsequent dose. The VE against notified pertussis was 96.4% (95% CI: 94.7, 97.6) for the first three doses of wP vaccine (2000–2007) and 95.7% (95% CI: 95.1, 96.2) for the first three doses of aP vaccine (2008–2019). ConclusionsOur findings suggested high levels of vaccine effectiveness overall were achieved for the aP and wP vaccines in Mexico between 2000 and 2019.

Humoral and Cellular Immunogenicity of 3 Doses of BNT162b2 in Children With Kidney Diseases

Patients with severe kidney diseases are at risk of complications from COVID-19; however, little is known about the effectiveness of COVID-19 vaccines in children and adolescents with kidney diseases. We investigated the immunogenicity and safety of an accelerated 3-dose primary series of COVID-19 vaccination among 59 pediatric patients with chronic kidney disease (CKD) (mean age 12.9 years; 30 male) with or without immunosuppression, dialysis, or kidney transplant. Dosage was 0.1 ml BNT162b2 to those aged 5 to 11 years, and 0.3 ml BNT162b2 to those aged 11 to 18 years. Three doses of either vaccine type elicited significant antibody responses that included spike receptor-binding domain (S-RBD) IgG (90.5%-93.8% seropositive) and surrogate virus neutralization (geometric mean sVNT% level, 78.6%-79.3%). There were notable T cell responses. Weaker neutralization responses were observed among those on immunosuppression, especially those receiving higher number of immunosuppressants or on mycophenolate mofetil. Neutralization was reduced against Omicron BA.1 compared to wild type (WT, i.e., ancestral) (post-dose 3 sVNT% level; 82.7% vs. 27.4%; P< 0.0001). However, the T cell response against Omicron BA.1 was preserved, which likely confers protection against severe COVID-19. Infected patients exhibited hybrid immunity after vaccination, as evidenced by the higher Omicron BA.1 neutralization response among these infected patients who received 2 doses compared with those who were uninfected. Generally mild or moderate adverse reactions following vaccines were reported. An accelerated 3-dose primary series with BNT162b2 is immunogenic and safe in young children and adolescents with kidney diseases.

Fourth mRNA COVID-19 vaccination in immunocompromised patients with haematological malignancies (COBRA KAI): a cohort study.

Patients with haematological malignancies have impaired antibody responses to SARS-CoV-2 vaccination. We aimed to investigate whether a fourth mRNA COVID-19 vaccination improved antibody quantity and quality. In this cohort study, conducted at 5 sites in the Netherlands, we compared antibody concentrations 28 days after 4 mRNA vaccinations (3-dose primary series plus 1 booster vaccination) in SARS-CoV-2 naive, immunocompromised patients with haematological malignancies to those obtained by age-matched, healthy individuals who had received the standard primary 2-dose mRNA vaccination schedule followed by a first booster mRNA vaccination. Prior to and 4 weeks after each vaccination, peripheral blood samples and data on demographic parameters and medical history were collected. Concentrations of antibodies that bind spike 1 (S1) and nucleocapsid (N) protein of SARS-CoV-2 were quantified in binding antibody units (BAU) per mL according to the WHO International Standard for COVID-19 serological tests. Seroconversion was defined as an S1 IgG concentration >10 BAU/mL and a previous SARS-CoV-2 infection as N IgG >14.3 BAU/mL. Antibody neutralising activity was tested using lentiviral-based pseudoviruses expressing spike protein of SARS-CoV-2 wild-type (D614G), Omicron BA.1, and Omicron BA.4/5 variants. This study is registered with EudraCT, number 2021-001072-41. Between March 24, 2021 and May 4, 2021, 723 patients with haematological diseases were enrolled, of which 414 fulfilled the inclusion criteria for the current analysis. Although S1 IgG concentrations in patients significantly improved after the fourth dose, they remained significantly lower compared to those obtained by 58 age-matched healthy individuals after their first booster (third) vaccination. The rise in neutralising antibody concentration was most prominent in patients with a recovering B cell compartment, although potent responses were also observed in patients with persistent immunodeficiencies. 19% of patients never seroconverted, despite 4 vaccinations. Patients who received their first 2 vaccinations when they were B cell depleted and the third and fourth vaccination during B cell recovery demonstrated similar antibody induction dynamics as patients with normal B cell numbers during the first 2 vaccinations. However, the neutralising capacity of these antibodies was significantly better than that of patients with normal B cell numbers after two vaccinations. A fourth mRNA COVID-19 vaccination improved S1 IgG concentrations in the majority of patients with a haematological malignancy. Vaccination during B cell depletion may pave the way for better quality of antibody responses after B cell reconstitution. The Netherlands Organisation for Health Research and Development and Amsterdam UMC.

Effectiveness of Tick-borne Encephalitis Vaccines in Children, Latvia, 2018-2020.

Tick-borne encephalitis (TBE) is an infection by the tick-borne encephalitis virus (TBEV) with symptoms of central nervous system inflammation. TBE is endemic in Latvia and other parts of Europe. TBE vaccination is recommended for children in Latvia. TBE vaccine effectiveness (VE) was estimated in Latvia, a country with high TBE incidence, providing the first VE estimates against a range of TBEV infection outcomes in children 1-15 years-of-age. Rīga Stradinš University conducted nationwide surveillance for suspected TBE cases. Serum and cerebrospinal fluid were ELISA tested for TBEV-specific IgG and IgM antibodies. A fully vaccinated child was an individual who had received the 3-dose primary series and appropriately timed boosters. The proportion of laboratory-confirmed TBE cases fully vaccinated (PCV) was determined from interviews and medical records. The proportion of the general population fully vaccinated (PPV) was determined from national surveys conducted in 2019 and 2020. TBE VE in children 1-15 years-of-age was estimated using the screening method: VE = 1 - [PCV/(1 - PCV)/PPV/(1 - PPV)]. From 2018 to 2020, surveillance identified 36 TBE cases in children 1-15 years-of-age; all were hospitalized, 5 (13.9%) for >12 days. Of the TBE cases, 94.4% (34/36) were unvaccinated compared with 43.8% of children in the general population. VE against TBE hospitalization in children 1-15 years-of-age was 94.9% (95% confidence interval 63.1-99.3). In 2018-2020, vaccination in children 1-15 years-of-age averted 39 hospitalized TBE cases. Pediatric TBE vaccines were highly effective in preventing TBE in children. Increasing TBE vaccine uptake in children is essential to maximize the public health impact of TBE vaccination.

Letter to the Editor: Women Doctors' Preferences Toward Neurosurgery Residency in Latin America— A Peruvian Perspective

The 7-valent pneumococcal conjugate vaccine (PCV7) was introduced into the routine immunization program in Uruguay in March 2008 with a 2-dose primary series (given at 2 and 4 months) plus a booster (at 12 months) and a catch-up campaign (two doses given at 15 and 17 months). We used a case–control methodology and existing laboratory surveillance and immunization registry data from Uruguay to evaluate PCV7 effectiveness against vaccine-type invasive pneumococcal disease (VT-IPD). Cases of VT-IPD (with pneumococcus obtained from a normally sterile site) were identified through the National Reference Laboratory. Age- and neighborhood-matched controls were obtained through a national immunization registry in which all children are enrolled at birth regardless of vaccine receipt; all eligible controls were included. Immunization status of cases and controls was assessed through the immunization registry, and conditional logistic regression was used to calculate PCV7 effectiveness. Between April 2008 and February 2010, 44 cases of VT-IPD among children < 5 years were identified; 43 (98%) of those children were located in the registry. Among located case patients, 7 (16.3%) were age-eligible to have received at least one dose of PCV7. A total of 637 matched controls were included. Vaccine effectiveness was 91.3% (95% CI: 46.4, 98.6) for ≥1 PCV7 doses and 94.8% (95% CI: 43.1, 99.5) for ≥2 PCV7 doses. Using existing data we demonstrated high effectiveness of PCV7 against VT-IPD in Uruguay–a middle-income country using a 2-dose primary series plus a booster dose and a limited catch-up campaign. These data also highlight the utility of surveillance and high-quality immunization registries for evaluating the effectiveness of vaccines.

Safety of a 2-dose primary series of 13-valent pneumococcal conjugate vaccine in Indonesian infants

BACKGROUND In 2017, the Indonesian Technical Advisory Group on Immunization recommended a safety monitoring demonstration program for the 13-valent pneumococcal conjugate vaccine (PCV13) in West Lombok and East Lombok, West Nusa Tenggara to evaluate the 2-dose primary series (2 and 3 months of age) for serious adverse events (SAEs), adverse events, systemic events, and local reactions.&#x0D; METHODS A total of 1,083 infants from 10 primary healthcare centers were analyzed, with 687 receiving the first dose and 396 receiving the second dose. Based on the national immunization program, they received PCV13 + DTwP-HB-Hib + OPV (n = 544), PCV13 + DTwP-HB-Hib (n = 101), or PCV13 only (n = 403). They were monitored for 30 min after vaccination for any immediate SAEs, and parents were given a diary card to record safety information prospectively for 28 days.&#x0D; RESULTS No immediate SAEs were observed, and no SAEs were reported during 28 days after vaccination. Reports of local reactions and systemic events predominated on days 1–3 post-vaccination. Severe fever (axillary temperature &gt;39.0°C) was uncommon (&lt;2% of all infants). Most irritability was mild to moderate. Local pain was more frequent after the first dose than after the second dose. It was distributed evenly across mild, moderate, and severe classifications, while redness and swelling were mostly mild to moderate.&#x0D; CONCLUSIONS The PCV13 primary series demonstration program in Indonesia confirmed tolerable local and systemic reactions.

Severe Acute Respiratory Syndrome Coronavirus 2 Vaccine Immunogenicity among Chimeric Antigen Receptor T Cell Therapy Recipients

Patients receiving chimeric antigen receptor T cell (CAR-T) therapy may have impaired humoral responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccinations owing to their underlying hematologic malignancy, prior lines of therapy, and CAR-T-associated hypogammaglobulinemia. Comprehensive data on vaccine immunogenicity in this patient population are limited. A single-center retrospective study of adults receiving CD19 or BCMA-directed CAR-T therapy for B cell non-Hodgkin lymphoma or multiple myeloma was conducted. Patients received at least 2 doses of SARS-CoV-2 vaccination with BNT162b2 or mRNA-1273 or 1 dose of Ad26.COV2.S and had SARS-CoV-2 anti-spike antibody (anti-S IgG) levels measured at least 1 month after the last vaccine dose. Patients were excluded if they received SARS-CoV-2 monoclonal antibody therapy or immunoglobulin within 3 months of the index anti-S titer. The seropositivity rate (assessed by an anti-S assay cutoff of ≥.8 U/mL in the Roche assay) and median anti-S IgG titers were analyzed. Fifty patients were included in the study. The median age was 65 years (interquartile range [IQR], 58 to 70 years), and the majority were male (68%). Thirty-two participants (64%) had a positive antibody response, with a median titer of 138.5 U/mL (IQR, 11.61 to 2541 U/mL). Receipt of ≥3 vaccines was associated with a significantly higher anti-S IgG level. Our study supports current guidelines for SARS-CoV-2 vaccination among recipients of CAR-T therapy and demonstrates that a 3-dose primary series followed by a fourth booster increases antibody levels. However, the relatively low magnitude of titers and low percentage of nonresponders demonstrates that further studies are needed to optimize vaccination timing and determine predictors of vaccine response in this population.

COVID-19 Vaccination Coverage and Demographic Characteristics of Infants and Children Aged 6 Months–4 Years — United States, June 20–December 31, 2022

Although severe COVID-19 illness and hospitalization are more common among older adults, children can also be affected (1). More than 3 million cases of COVID-19 had been reported among infants and children aged <5 years (children) as of December 2, 2022 (2). One in four children hospitalized with COVID-19 required intensive care; 21.2% of cases of COVID-19-related multisystem inflammatory syndrome in children (MIS-C) occurred among children aged 1-4 years, and 3.2% of MIS-C cases occurred among infants aged <1 year (1,3). On June 17, 2022, the Food and Drug Administration issued an Emergency Use Authorization (EUA) of the Moderna COVID-19 vaccine for children aged 6 months-5 years and the Pfizer-BioNTech COVID-19 vaccine for children aged 6 months-4 years. To assess COVID-19 vaccination coverage among children aged 6 months-4 years in the United States, coverage with ≥1 dose* and completion of the 2-dose or 3-dose primary vaccination series† were assessed using vaccine administration data for the 50 U.S. states and District of Columbia submitted from June 20 (after COVID-19 vaccine was first authorized for this age group) through December 31, 2022. As of December 31, 2022, ≥1-dose COVID-19 vaccination coverage among children aged 6 months-4 years was 10.1% and was 5.1% for series completion. Coverage with ≥1 dose varied by jurisdiction (range=2.1% [Mississippi] to 36.1% [District of Columbia]) as did coverage with a completed series (range=0.7% [Mississippi] to 21.4% [District of Columbia]), respectively. By age group, 9.7 % of children aged 6-23 months and 10.2% of children aged 2-4 years received ≥1 dose; 4.5% of children aged 6-23 months and 5.4% of children aged 2-4 years completed the vaccination series. Among children aged 6 months-4 years, ≥1-dose COVID-19 vaccination coverage was lower in rural counties (3.4%) than in urban counties (10.5%). Among children aged 6 months-4 years who received at least the first dose, only 7.0% were non-Hispanic Black or African American (Black), and 19.9% were Hispanic or Latino (Hispanic), although these demographic groups constitute 13.9% and 25.9% of the population, respectively (4). COVID-19 vaccination coverage among children aged 6 months-4 years is substantially lower than that among older children (5). Efforts are needed to improve vaccination coverage among children aged 6 months-4 years to reduce COVID-19-associated morbidity and mortality.

784. Real-world effectiveness of the mRNA-12733-dose primary series against COVID-19 in an immunocompromised population Interim results from a prospective observational cohort study

Abstract Background While a 3-dose mRNA-1273 primary series is recommended for moderately or severely immunocompromised (IC) individuals in the U.S., some IC individuals do not complete the 3-dose series. We conducted a matched cohort study to evaluate the relative vaccine effectiveness (rVE) of the 3-dose mRNA-1273 primary series vs. 2 doses of mRNA-1273 in preventing SARS-CoV-2 infection and severe COVID-19 disease in IC individuals. Methods IC individuals aged ≥18 years with ≥12 months of Kaiser Permanente Southern California membership who received 3 doses of mRNA-1273 ≥24 days apart were 1:1 matched with randomly selected IC 2-dose recipients on age, sex, race/ethnicity, and 2nd dose date. Third doses were accrued from 08/12/2021 to 12/31/2021, with follow-up through 1/31/2022, spanning the delta and omicron periods. Outcomes were SARS-CoV-2 infection (positive molecular test or diagnosis code), COVID-19 hospitalization, and COVID-19 hospital death. Adjusted hazard ratios (aHR) with confidence intervals (CI) were estimated by Cox proportional hazards models. Adjusted rVE (%) was calculated as (1-aHR) x 100. Results Our study included 21,942 3-dose and 21,942 2-dose mRNA-1273 IC recipients. Adjusted rVE of 3 doses compared to 2 doses of mRNA-1273 against SARS-CoV-2 infection, COVID-19 hospitalization, and COVID-19 hospital death were 55.0% (95% CI: 50.8–58.9%), 83.0% (75.4–88.3%), and 87.1% (30.6–97.6%), respectively (Table 1). Adjusted rVE against SARS-CoV-2 infection ranged from 43.0% to 59.1% across subgroups of age, sex, race/ethnicity, history of SARS-CoV-2 infection, pregnancy, and comorbidities (Table 2). Point estimates of the 3-dose rVE were higher against COVID-19 infection and hospitalization in the first 3 months, compared to 3–6 months after the 3rd dose (Table 3). Conclusion Three doses of mRNA-1273 provide additional protection against SARS-CoV-2 infection and severe outcomes for IC individuals, compared to 2 doses, highlighting the importance of completing 3-doses for IC populations. However, possible waning of protection against SARS-CoV-2 infection and severe outcomes after 3 months supports the ACIP recommendation of a booster dose at least 3 months after the 3rd primary series dose for adequate protection of IC individuals. Disclosures Jennifer H. Ku, PhD MPH, GSK: Grant/Research Support|Moderna: Grant/Research Support Lina S. Sy, MPH, Dynavax: Grant/Research Support|Glaxosmithkline: Grant/Research Support|Moderna: Grant/Research Support|Seqirus: Grant/Research Support Lei Qian, PhD, Dynavax: Grant/Research Support|Glaxosmithkline: Grant/Research Support|Moderna: Grant/Research Support Bradley Ackerson, MD, Dynavax: Grant/Research Support|Glaxosmithkline: Grant/Research Support|Moderna: Grant/Research Support|Pfizer: Grant/Research Support|Seqirus: Grant/Research Support Yi Luo, PhD, Glaxosmithkline: Grant/Research Support|Moderna: Grant/Research Support|Pfizer: Grant/Research Support|Seqirus: Grant/Research Support Julia Tubert, MPH, Moderna: Grant/Research Support|Pfizer: Grant/Research Support Gina Lee, MPH, Glaxosmithkline: Grant/Research Support|Moderna: Grant/Research Support Ana Florea, PhD MPH, Gilead: Grant/Research Support|GSK: Grant/Research Support|Moderna: Grant/Research Support|Pfizer: Grant/Research Support Carla Talarico, PhD, Moderna: Employee of and a shareholder in Moderna Inc. Sijia Qiu, MS, Dynavax: Grant/Research Support|Moderna: Grant/Research Support Yun Tian, MS, Glaxosmithkline: Grant/Research Support|Moderna: Grant/Research Support Hung Fu Tseng, PhD MPH, GSK: Grant/Research Support|Janssen: Advisor/Consultant|Moderna: Grant/Research Support|Pfizer: Advisor/Consultant|Seqirus: Grant/Research Support.

1953. Immune responses, viral shedding, and COVID-19 symptom burden from breakthrough SARS-CoV-2 infection in a 2:1 randomized, double-blind, placebo-controlled Phase 3 study of AZD1222 (ChAdOx1 nCoV-19) vaccination

Abstract Background Breakthrough infections post-COVID-19 vaccination increase with waning immunity and typically produce milder disease than infections in unvaccinated individuals. We investigated immuno-virologic responses and COVID-19 symptom burden upon breakthrough infection in participants from a Phase 3 study of 2-dose primary series AZD1222 vaccination (NCT04516746) to explore disease attenuation. Methods Study participants who experienced protocol-defined COVID-19 symptoms initiated a series of illness visits over 28 days with collection of sera, nasopharyngeal (NP) swabs and saliva samples (SS), and documentation of symptoms (data-cut off: July 30, 2021). For baseline-seronegative participants with PCR-confirmed SARS-CoV-2 infection ≥15 days after dose 2 of AZD1222 or placebo we assessed: anti-SARS-CoV-2 spike (S), nucleocapsid (N) and neutralizing antibody (Ab) titers by multiplex immunoassay and SARS-CoV-2 pseudovirus assay in sera; viral load by quantitative RT-PCR in NP swabs; and viral shedding by qualitative and quantitative RT-PCR in SS. Data were stratified by age and SARS-CoV-2 variant, and time since primary series dose 2. Results Illness Day 1 (ILL-D1) S Ab GMTs in AZD1222 vaccinees were similar to peak GMTs seen 14 days after dose 2 of AZD1222 and were higher vs placebo at all timepoints. The magnitude of S Ab response differed by age: median GMTs were lower at ILL-D1 and higher at ILL-D14 in vaccinees aged ≥65 vs 18–64 years (Fig.1). ILL-D1 overall, SARS-CoV-2 ancestral, alpha, and epsilon variant viral load titers in NP swabs were lower in vaccinees vs placebo (Fig 2). Mean viral load in NP swabs and viral shedding titers in SS were lower in vaccinees vs placebo at all timepoints. Vaccinees reported fewer COVID-19 symptoms than placebo participants, and experienced shorter symptom duration, particularly for fatigue and difficulty breathing. Figure 1. SARS-CoV-2 spike IgG antibody titers upon SARS-CoV-2 infection by participant age in AZD1222 vaccinees and placebo recipients during illness visits Figure 2. Quantification of viral load (nasopharyngeal swabs quantitative viral titer) by SARS-CoV-2 variant at Illness Visit Day 1 Conclusion Improved S Ab responses, lower viral loads, and reduced symptom burden upon breakthrough infection in vaccinees vs placebo recipients, suggest that robust recall responses to AZD1222 vaccination may attenuate COVID-19 disease severity and duration. These findings alongside data on cellular immune responses to breakthrough infection will inform understanding of protective immunity to SARS-CoV-2 infection. Disclosures Magdalena E. Sobieszczyk, MD, MPH, Bill and Melinda Gates Foundation: Grant/Research Support|Gilead Sciences: Grant/Research Support|Janssen Global Services, LLC: Grant/Research Support|Merck: Grant/Research Support|National Institute of Allergy and Infectious Diseases (NIAID): Grant/Research Support|National Institutes of Health (NIH): Grant/Research Support|Sanofi Pasteur Inc.: Grant/Research Support Ann R. Falsey, MD, BioFire Diagnostics: Grant/Research Support|Janssen: Grant/Research Support|Merck, Sharp and Dohme: Grant/Research Support|Novavax: Advisor/Consultant|Pfizer: Grant/Research Support Anne F. Luetkemeyer, MD, AstraZeneca: Grant/Research Support|Gilead Sciences: Grant/Research Support Grant C. Paulsen, MD, AstraZeneca: Grant/Research Support|Moderna: Grant/Research Support|Pfizer: Grant/Research Support Sharon A. Riddler, MD, National Institute of Allergy and Infectious Diseases (NIAID): Grant/Research Support|National Institutes of Health (NIH): Grant/Research Support|Novimmune: Advisor/Consultant Merlin L. Robb, MD, Walter Reed Army Institute of Research: Advisor/Consultant Charlotte-Paige M. Rolle, MD, MPH, Gilead Sciences: Board Member|Gilead Sciences: Grant/Research Support|Gilead Sciences: Honoraria|Janssen: Board Member|ViiV Healthcare: Board Member|ViiV Healthcare: Grant/Research Support|ViiV Healthcare: Honoraria|Vindico CME: Honoraria Beverly E. Sha, MD, Gilead Sciences: Grant/Research Support|MATEC: Honoraria|University of Chicago: Grant/Research Support|US Government: Grant/Research Support Bahar Ahani, BSC, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Anastasia A. Aksyuk, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Himanshu Bansal, MS, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Justin A. Green, MD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Brett Jepson, MS, AstraZeneca: Contractor via Cytel Jill Maaske, MD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Kathryn Shoemaker, MS, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Stephanie Sproule, MMath, AstraZeneca: Contractor via Joule/System One Ann Marie Stanley, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Deidre Wilkins, BSC, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Tonya L. Villafana, PhD, MPH, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Elizabeth J. Kelly, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds.

Effectiveness of mRNA Booster Vaccination Against Mild, Moderate, and Severe COVID-19 Caused by the Omicron Variant in a Large, Population-Based, Norwegian Cohort.

Understanding how booster vaccination can prevent moderate and severe illness without hospitalization is crucial to evaluate the full advantage of mRNA boosters. We followed 85 801 participants (aged 31-81 years) in 2 large population-based cohorts during the Omicron BA.1/2 wave. Information on home testing, PCR testing, and symptoms of coronavirus disease 2019 (COVID-19) was extracted from biweekly questionnaires covering the period 12 January 2022 to 7 April 2022. Vaccination status and data on previous SARS-CoV-2 infection were obtained from national registries. Cox regression was used to estimate the effectiveness of booster vaccination compared to receipt of 2-dose primary series >130 days previously. The effectiveness of booster vaccination increased with increasing severity of COVID-19 and decreased with time since booster vaccination. The effectiveness against severe COVID-19 was reduced from 80.9% shortly after booster vaccination to 63.4% in the period >90 days after vaccination. There was hardly any effect against mild COVID-19. The effectiveness tended to be lower among subjects aged ≥60 years than those aged <50 years. This is the first population-based study to evaluate booster effectiveness against self-reported mild, moderate, and severe COVID-19. Our findings contribute valuable information on duration of protection and thus timing of additional booster vaccinations.

Correlation of Postvaccination Fever With Specific Antibody Response to Severe Acute Respiratory Syndrome Coronavirus 2 BNT162b2 Booster and No Significant Influence of Antipyretic Medication.

BackgroundA severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine booster elicits sufficient antibody responses that protect against coronavirus disease 2019, whereas adverse reactions such as fever have been commonly reported. Associations between adverse reactions and antibody responses have not been fully characterized, nor has the influence of antipyretic use.MethodsThis is a prospective observational cohort study in Japan, following our prior investigation of BNT162b2 2-dose primary series. Spike-specific immunoglobulin G (IgG) titers were measured for SARS-CoV-2–naive hospital healthcare workers who received a BNT162b2 booster. The severity of solicited adverse reactions, including the highest body temperature, and self-medicated antipyretics were reported daily for 7 days following vaccination through a web-based self-reporting diary.ResultsThe data of 281 healthcare workers were available. Multivariate analysis extracted fever after the booster dose (β = .305, P < .001) as being significantly correlated with the specific IgG titers. The analysis of 164 participants with data from the primary series showed that fever after the second dose was associated with the emergence of fever after the booster dose (relative risk, 3.97 [95% confidence interval, 2.48–6.35]); however, the IgG titers after the booster dose were not associated with the presence or degree of fever after the second dose. There were no significant differences in the IgG titers by the use, type, or dosage of antipyretic medication.ConclusionsThese results suggest an independent correlation between mRNA vaccine–induced specific IgG levels and post–booster vaccination fever, without any significant influence of fever after the primary series. Antipyretic medications for adverse reactions should not interfere with the elevation of specific IgG titers.

Effectiveness of Messenger RNA-1273 Vaccine Booster Against Coronavirus Disease 2019 in Immunocompetent Adults.

We conducted a prospective cohort study at Kaiser Permanente Southern California to evaluate the relative vaccine effectiveness (rVE) of a booster dose vs 2-dose primary series of messenger RNA (mRNA)-1273 in immunocompetent individuals. Immunocompetent adults who received a booster dose of mRNA-1273 from October 2021 through December 2021 were matched 1:1 to randomly selected 2-dose mRNA-1273 recipients by age, sex, race/ethnicity, and second-dose date and followed up through January 2022. Cox proportional hazards models were used to estimate adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs), comparing outcomes (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] infection and coronavirus disease 2019 [COVID-19] hospitalization and hospital death) in the booster-dose and 2-dose groups. Adjusted rVE (%) was calculated as (1 - aHR) × 100. aHRs and rVE were also estimated by subgroup and month of follow-up. The study included 431 328 booster-dose vaccinated adults matched to 431 328 2-dose vaccinated adults. rVE was 61.3% (95% CI: 60.5%-62.2%) against SARS-CoV-2 infection, 89.0% (86.2%-91.2%) against COVID-19 hospitalization, and 96.0% (68.0%-99.5%) against COVID-19 hospital death. rVE against SARS-CoV-2 infection ranged from 55.6% to 66.7% across all subgroups. rVE against SARS-CoV-2 infection decreased from 67.1% (0 to <1 month of follow-up) to 30.5% (2 to <3 months). For COVID-19 hospitalization, rVE decreased from 91.2% (0 to <1 month) to 78.7% (2 to <3 months). Among immunocompetent adults, the mRNA-1273 booster conferred additional protection against SARS-CoV-2 infection and severe COVID-19 disease compared with the 2-dose mRNA-1273 primary series during periods of Delta and Omicron predominance.

Immunogenicity of a Three-Dose Primary Series of mRNA COVID-19 Vaccines in Patients With Lymphoid Malignancies.

BackgroundPatients with lymphoid malignancies are at risk for poor coronavirus disease 2019 (COVID-19)-related outcomes and have reduced vaccine-induced immune responses. Currently, a 3-dose primary regimen of mRNA vaccines is recommended in the United States for immunocompromised hosts.MethodsA prospective cohort study of healthy adults (n = 27) and patients with lymphoid malignancies (n = 94) was conducted, with longitudinal follow-up through completion of a 2- or 3-dose primary mRNA COVID vaccine series, respectively. Humoral responses were assessed in all participants, and cellular immunity was assessed in a subset of participants.ResultsThe rate of seroconversion (68.1% vs 100%) and the magnitude of peak anti-S immunoglobulin G (IgG) titer (median anti-S IgG = 32.4, IQR = 0.48–75.0 vs median anti-S IgG = 72.6, IQR 51.1–100.1; P = .0202) were both significantly lower in patients with lymphoid malignancies compared to the healthy cohort. However, peak titers of patients with lymphoid malignancies who responded to vaccination were similar to healthy cohort titers (median anti-S IgG = 64.3; IQR, 23.7–161.5; P = .7424). The third dose seroconverted 7 of 41 (17.1%) patients who were seronegative after the first 2 doses. Although most patients with lymphoid malignancies produced vaccine-induced T-cell responses in the subset studied, B-cell frequencies were low with minimal memory cell formation.ConclusionsA 3-dose primary mRNA series enhanced anti-S IgG responses to titers equivalent to healthy adults in patients with lymphoid malignancies who were seropositive after the first 2 doses and seroconverted 17.1% who were seronegative after the first 2 doses. T-cell responses were present, raising the possibility that the vaccines may confer some cell-based protection even if not measurable by anti-S IgG.

Relative effectiveness of booster vs. 2-dose mRNA Covid-19 vaccination in the Veterans Health Administration: Self-controlled risk interval analysis

ObjectiveTo estimate relative effectiveness of the booster mRNA Covid-19 vaccination versus the 2-dose primary series for both Delta and Omicron variants with self-controlled study design. MethodsWe used the Veterans Health Administration (VHA) Corporate Data Warehouse to identify U.S. Veterans who received the 2-dose primary mRNA Covid-19 vaccine series and a mRNA Covid-19 booster, and who had a positive SARS-CoV-2 test during the Delta (9/23/2021–11/30/2021) or Omicron (1/1/22–3/19/22) predominant period. Among them, we conducted a self-controlled risk interval (SCRI) analysis to compare odds of SARS-CoV-2 infection during a booster exposure interval versus a control interval. Exposures were a control interval (days 4–6 post-booster vaccination, presumably prior to gain of booster immunity), and booster exposure interval (days 14–16 post-booster vaccination, presumably following gain of booster immunity). Cases had a positive PCR or antigen SARS-CoV-2 test. Separately for Delta and Omicron periods, we used conditional logistic regression to calculate odds ratios (OR) of a positive test for the booster versus control interval and calculated relative effectiveness of booster versus 2-dose primary series as (1-OR)*100. The SCRI approach implicitly controlled for time-fixed confounders. ResultsWe found 42 individuals with a positive SARS-CoV-2 test in the control interval and 14 in the booster exposure interval during the Delta period, and 141 and 70, respectively, in the Omicron period. For the booster versus 2-dose primary series, the odds of infection were 70% (95 %CI: 42%, 84%) lower during the Delta period and 54% (95 %CI: 38%, 66%) lower during Omicron. In sensitivity analyses among those with prior Covid-19 history, and age stratification, ORs were similar to the main analysis. ConclusionsBooster vaccination was more effective relative to a 2-dose primary series during the Delta and Omicron predominant periods, and the relative effectiveness was consistent across age groups.

Relative Effectiveness of COVID-19 Vaccination in Healthcare Workers: 3-Dose Versus 2-Dose Vaccination.

The omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is known to have high infectivity and is more likely to evade vaccine immunity. However, booster vaccination is expected to strengthen cross-reactive immunity, thereby increasing the vaccine effectiveness (VE). This study aimed to evaluate the relative VE of the 3-dose (booster) vaccination compared with the 2-dose primary series vaccination in healthcare workers during omicron variant-dominant periods. During the omicron-dominant period from February 1, 2022 to February 28, 2022, a 1:1 matched case-control study was conducted. Healthcare workers with positive SARS-CoV-2 test results were classified as positive cases, whereas those with negative results served as controls. Compared with the 2-dose primary series vaccination, booster vaccination with mRNA vaccine showed moderate VE (53.1%). However, in multivariate analysis including the time elapsed after vaccination, the significant VE disappeared, reflecting the impact of recent vaccination rather than the third dose itself.