Vaccine

Background and ObjectiveBells palsy (BP) has been considered as a serious adverse event following the SARS-CoV-2 vaccination. Many studies have reported BP following vaccination, although neither a causative relationship nor a prevalence of the condition higher than the general population has been established. The outcomes of interest were to compare BP incidence among (a) SARS-CoV-2 vaccine recipients, (b) nonrecipients in the placebo or unvaccinated cohorts, (c) different types of SARS-CoV-2 vaccines, and (d) SARS-CoV-2 infected vs. SARS-CoV-2 vaccinated individuals. MethodsWe performed a systematic search through MEDLINE (via PubMed), Web of Science, Scopus, Cochrane library, and Google Scholar from the inception to August 15, 2022. We included articles reporting individuals receiving any SARS-CoV-2 vaccine in whom BP had occurred. Studies reporting facial paralysis due to etiologies other than BP were excluded. Random- and fixed-effects meta-analyses using the Mantel-Haenszel method were conducted for the quantitative synthesis. Newcastle-Ottawa scale (NOS) was used to assess the quality. The study was conducted in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline, and the protocol was registered with PROSPERO (CRD42022313299). Analyses were carried out using the R, version 4.2.1 (R package meta version 5.2-0). ResultsFifty studies were included, of which 17 entered the quantitative synthesis. First, pooling four phase-3 randomized controlled trials (RCT) indicated BP occurrence was significantly higher in SARS-CoV-2 vaccines (77, 525 doses) compared to placebo (66, 682 doses) (OR = 3.00, 95% CI = 1.10 - 8.18, I2 = 0%). Second, pooling nine observational studies of mRNA SARS-CoV-2 vaccine doses (13, 518,026) and matched unvaccinated individuals (13, 510,701) revealed no significant increase in the odds of BP in the vaccinated group compared to the unvaccinated group (OR: 0.70 (95% CI 0.42-1.16), I2=94%). The third meta-analysis suggested that post-vaccination BP among first dose Pfizer/BioNTech recipients (22,760,698) did not significantly differ from that in first dose Oxford/AstraZeneca recipients (22,978,880) (OR = 0.97, 95% CI = 0.82 - 1.15, I2 = 0%). According to the fourth meta-analysis, BP was significantly more commonly reported after SARS-CoV-2 infection (2,641,398) than after SARS-CoV-2 vaccinations (36,988,718) (RR = 4.03, 95% CI = 1.78 - 9.12, I2 = 96%). ConclusionOur meta-analysis suggests a higher incidence of BP among vaccinated vs. placebo groups. BP occurrence did not significantly differ between Pfizer/BioNTech and Oxford/AstraZeneca vaccines. SARS-CoV-2 infection posed a significantly greater risk for BP than SARS-CoV-2 vaccines.

BackgroundWe previously identified Bordetella pertussis-derived outer membrane vesicles (OMVs) as a promising immunogen for improving pertussis vaccines. In this study, we evaluated the efficacy of our vaccine prototype in immunization strategies aimed at reducing disease transmission by targeting colonization in the upper airways while maintaining protection against severe disease by reducing colonization in the lower respiratory tract. MethodsWe assessed different mucosal administration strategies in a murine model, including homologous 2-dose schedules and heterologous prime-boost strategies combining intramuscular (IM) systemic immunization with mucosal routes (intranasal (IN) or sublingual (SL)). We utilized mucosal c-di-AMP and/or systemic alum adjuvants to formulate the OMV vaccine prototype. A homologous IM immunization schedule and commercial vaccines were used for comparison. ResultsAll tested heterologous schemes induced higher levels of specific IgG with significant avidity, as well as high levels of IgG1 and IgG2 compared, to corresponding homologous 2-dose schemes via mucosal routes (OMVIN-IN or OMVSL-SL). High IgA levels were observed post-B. pertussis challenge following OMVIN-IN treatments and heterologous treatments where the second dose was administered via a mucosal route. Furthermore, schemes involving the intranasal route, whether in a homologous or heterologous scheme, induced the highest levels of IL-17 and IFN-{gamma}. Accordingly, these schemes showed superior efficacy against nasal colonization than the commercial vaccines. Specifically, homologous intranasal immunization exhibited the highest protective capacity against nasal colonization while maintaining an excellent level of protection in the lower respiratory tract. To enhance the protective capacity against nasal colonization further, we conducted a comparative analysis of formulations containing different adjuvants (c-di-AMP, alum, or a combination of both) administered via homologous intranasal routes. These assays revealed that the use of alum, either alone or in combination with c-di-AMP, did not enhance the immune protective capacity. ConclusionsAll the experiments presented here highlight that the use of OMVs, regardless of the scheme utilized, with the exception of OMVSL-SL, outperformed acellular pertussis (aP) vaccines, achieving a greater reduction in bacterial colonization in the upper respiratory tract (p<0.001).

3.1Pertussis is a vaccine-preventable respiratory disease caused by the Gram-negative bacterium Bordetella pertussis. While vaccination rates remain high in developed countries, incidence of pertussis has increased following the transition from wP vaccines to aP vaccines. The reemergence of pertussis is attributed, in part, to waning immunity induced by aP vaccination. Therefore, the objective of this work was to determine if addition of adjuvant to DTaP can modulate the immune response and improve protection compared to DTaP alone. In this study we immunized outbred, female CD-1 mice with 1/320th the human dose of vehicle control, DTaP, and DTaP supplemented with adjuvant. Markers of early vaccine-induced memory were measured using a chemokine assay or by flow cytometry. Protection was assessed by measuring serological responses and quantifying bacterial burden in the respiratory tract at day 3 post-challenge. From this work we identified a partially protective aP vaccine dose to use for vaccination and challenge studies. We observed that MPLA and SWE promote robust anti-B. pertussis antibody responses and stimulate significant increases in early markers of vaccine-induced memory such as CXCL13, FDCs, and TFH cells. Quil-A induced Th1 responses compared to DTaP alone, but none of the adjuvants improved protection against challenge with B. pertussis. Overall, the data suggests that addition of adjuvant modulates the protective immune responses induced by aPs. Further studies are needed to evaluate the B cell compartment and longevity of protection.

ObjectiveA model conjugate vaccine incorporating a pneumococcal polysaccharide with EcoCRM197 was used to determine vaccine efficacy when administered with our clinical-stage mucosal stimulating adjuvant, NE01. This was the first attempt at combining NE01 with a polysaccharide conjugate vaccine to elicit mucosal immunity against respiratory bacterial infection through intranasal immunizations. ResultsIntranasal immunizations using the NE01 adjuvant incorporating a polysaccharide conjugate resulted in the generation of a robust IgG and IgA responses in both serum and mucosa. Our data also demonstrated the active homing of immunological memory cells to the lower respiratory tract as evidenced by an increase of IgG- and IgA-producing memory B-cells in the lungs. Further, intranasal immunization enhanced the induction of a balanced Th1/Th2/ Th17 immune response with clear homing of memory T-cells to the lungs. Serum antibodies generated by this formulation and route of administration demonstrated excellent efficacy in killing S. pneumonia in an in vitro OPK assay, a biomarker of vaccine efficacy. Our data suggest that further optimization of the dose and schedule as well as evaluation of the efficacy of this new formulation in animal models of colonization and infection are warranted.

Few studies have assessed the impact of the COVID-19 pandemic on immunization coverage for adolescents, and little is known about how coverage has changed throughout the pandemic. We aimed to: (1) assess the change in coverage for school-based vaccines in Alberta, Canada resulting from the pandemic; (2) determine whether coverage differed by geographic health zone and school type; and (3) ascertain whether coverage has returned to pre-pandemic levels. Using a retrospective cohort design, we used administrative health data to compare coverage for human papillomavirus (HPV) and meningococcal conjugate A, C, Y, W-135 (MenC-ACYW) vaccines in Alberta, Canada between pre-pandemic (2017-2018 school year) and pandemic (2019-2020 and 2020-2021 school years) cohorts (N=289,420). Coverage was also compared by health zone and authority type. The 2019-2020 cohort was followed over one year to assess catch-up. Compared to 2017-2018, immunization coverage for HPV was significantly lower in the 2019-2020 (absolute difference: 60.8%; 95% CI: 60.4-61.3%) and 2020-2021 cohorts (absolute difference: 59.9%; 95% CI: 59.4-60.3%). There was a smaller, significant decline in MenC-ACYW coverage comparing 2017-2018 to 2019-2020 (absolute difference: 6.1%; 95% CI: 5.6-6.5%) and 2020-2021 (absolute difference: 32.2%; 95% CI: 31.6-32.7%). Private schools had low coverage overall, while coverage fluctuated by zone. During follow-up of the 2019-2020 cohort, coverage for HPV and MenC-ACYW increased from 5.6% to 50.2%, and 80.7% to 83.0%, respectively. There was a substantial decrease in school-based immunization coverage during the COVID-19 pandemic, and coverage has not returned to pre-pandemic levels, suggesting further catch-up is needed.

AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSHypothesisC_ST_ABSThis study investigates whether U.S. Centers for Disease Control and Prevention Vaccine Adverse Events Reporting System (VAERS) data suggest an association between vertigo, tinnitus, hearing loss, Bells palsy and the COVID-19 vaccines administered in the United States. BackgroundPublished case reports suggest a possible association between various otologic symptoms and the COVID-19 vaccines, but the only published analysis of VAERS data, which did not account for underreporting of late-appearing adverse events, found no association between hearing loss and the vaccines. MethodsThe incidence in VAERS of vertigo, tinnitus, hearing loss, and Bells palsy associated with COVID-19 vaccinations administered between December 14, 2020 and June 7, 2021 was compared with published rates for the general population. To account for underreporting of late-appearing adverse events, incidences were calculated using only the initial part of the observation period, during which reported events spike above expected events. ResultsThe COVID-19 vaccines were associated with statistically significant increases in the incidence of vertigo, tinnitus, hearing loss, and Bells palsy of 1877, 50, 12, and 14 cases per 100,000, respectively. In relation to the mRNA-1273 or BNT162b2 vaccines, the Ad26.COV2.S vaccine was associated with a statistically significant excess incidence of vertigo, tinnitus, and hearing loss of at least 723, 57, and 55 cases per 100,000, respectively. ConclusionThese results suggest an association between the COVID-19 vaccines and vertigo, tinnitus, hearing loss, and Bells palsy. They also suggest that, with respect to vertigo, tinnitus, and hearing loss, the association is relatively strong for the Ad26.COV2.S vaccine.

Participants in studies investigating COVID-19 vaccines commonly report reactogenicity events, and concerns about side effects may lead to reluctance to receive updated COVID-19 vaccinations. A real-world, post hoc analysis, observational 2019nCoV-406 study, was conducted to examine reactogenicity within the first 2 days after vaccination with either a protein-based vaccine (NVX-CoV2373) or an mRNA vaccine (BNT162b2 or mRNA-1273) in individuals who previously completed a primary series. Propensity score adjustments were conducted to address potential confounding. The analysis included 1130 participants who received a post-primary series dose of NVX-CoV2373 (n = 303) or an mRNA vaccine (n = 827) during the study period. Within the first 2 days after vaccination, solicited systemic reactogenicity events (adjusted) were reported in 60.5% of participants who received NVX-CoV2373 compared with 84.3% of participants who received an mRNA vaccine; moreover, 33.9% and 61.4%, respectively, reported [&ge;]3 systemic reactogenicity symptoms. The adjusted mean (95% CI) number of systemic symptoms was 1.8 (1.6-2.0) and 3.2 (3.0-3.4), respectively. Local reactogenicity events (adjusted) were reported in 73.4% and 91.7% of participants who received NVX-CoV2373 and mRNA vaccines, respectively; the adjusted mean (95% CI) number of local symptoms was 1.5 (1.33-1.61) and 2.4 (2.31-2.52), respectively. These results support the use of adjuvanted, protein-based NVX-CoV2373 as an immunization option with low reactogenicity.

BackgroundWhole-cell pertussis (wP) and acellular pertussis (aP) vaccines evoke different immune responses to pertussis vaccine antigens. We compared the effect of a heterologous wP/aP/aP primary series (hereafter mixed wP/aP) versus a homologous aP/aP/aP primary schedule (hereafter aP-only) on antibody responses to co-administered vaccine antigens in infants and toddlers. MethodsWe randomised Australian infants in a 1:1 ratio to receive either a mixed wP/aP schedule (pentavalent diphtheria-tetanus-wP-hepatitis B-Haemophilus influenzae type b; DTwP-HepB-Hib vaccine at 6 weeks old followed by hexavalent DTaP-inactivated poliovirus vaccine (IPV)-HepB-Hib vaccine at 4 and 6 months old) or to aP-only priming doses of hexavalent DTaP-IPV-HepB-Hib vaccine at the same ages. All infants received 13-valent pneumococcal conjugate vaccine (13vPCV) at 6 weeks, 4 and 12 months of age and DTaP-IPV and Hib vaccine boosters at 18 months. We estimated the ratio (GMR) of IgG geometric mean concentrations (GMCs) in the wP/aP and aP-only groups for the serotypes included in the 13vPCV, for Hib capsular polysaccharide polyribosylribitol phosphate (PRP), and for hepatitis B surface antigen (HBsAg) at 6, 7, 18, and 19 months. We assessed whether the wP/aP schedule is non-inferior to the aP-only schedule for co-administered vaccine antigens (GMR>2/3). Trial registration: ACTRN12617000065392p. ResultsBetween March 2018 and January 2020, 150 infants were randomised (75 per study arm). Responses to all 13vPCV serotypes and Hib-PRP at 6, 7, 18, and 19 months old, as well as HBsAg at 6 and 7 months old were non-inferior (>90% probability). Sera GMCs were higher for each 13vPCV serotype, Hib-PRP, and HBsAg at each timepoint in the wP/aP group than in the aP-only group. InterpretationA mixed wP/aP schedule resulted in non-inferior IgG responses to co-administered vaccine antigens compared to the standard aP-only schedule for pertussis primary immunisation. FundingTelethon New Childrens Hospital Research Fund and National Health and Medical Research Council. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSCombination vaccines incorporate antigens that protect against multiple diseases into a single injection. Most low- and middle-income countries (LMICs) currently use wP combination vaccines. Due to the need for periodic boosters to protect older children, adolescents, and adults, these countries may consider moving to the less reactogenic aP combination vaccines that are routinely used in most high-income countries. We searched for evidence about whether a mixed wP/aP primary schedule impacts the immunogenicity of co-administered vaccines. We were particularly interested in evidence for impacts on 13vPCV 2 + 1 schedule and other pneumococcal dose-sparing schedules. We searched PubMed on May 23, 2024, for randomised controlled trials using the following search terms "pneumococcal", "routine vaccin*", and "pertussis" combined with Boolean operators, without date or language restrictions. We failed to identify any head-to-head randomised comparisons of the effect of heterologous (mixed) versus homologous pertussis vaccine primary series on co-administered vaccine antigens. Our previous meta-analysis reviewed 15 randomised controlled studies that compared serious adverse events among infants receiving wP versus aP as a first dose before 6 months of age. Few studies reported immune responses to non-DTP co-administered antigens. These findings suggest enhanced Hib responses among recipients of a three-dose primary series of wP compared to those who received three primary aP doses, non-inferior Hib-PRP seroprotection among aP compared to wP vaccinees, and mixed results regarding HBsAg-IgG levels post-wP priming. Both wP and aP groups exhibited weaker Hib-PRP IgG responses when DTP-Hib vaccines were co-administered with meningococcal serogroup C vaccine conjugated to cross-reactive material 197 (CRM197) compared to the meningococcal serogroup C vaccine conjugated to tetanus toxoid (TT). Added value of this studyThis paper is the first reported evidence of a mixed wP/aP schedule resulting in non-inferior IgG responses to co-administered vaccine antigens compared to the standard homologous aP-only schedule for pertussis primary immunisation. In addition, enhanced immune responses were observed to all serotypes included in the 13vPCV and Hib-PRP vaccines in children receiving the mixed wP/aP vaccination strategy versus those vaccinated with a standard aP-only schedule. Implications of all the available evidenceIn settings transitioning from using wP to aP multi-component vaccines, infants receiving a mixed schedule (with wP as the first dose) can be expected have non-inferior, and possibly superior, antibody responses to concomitant vaccine antigens. To better understand the underlying mechanisms of our findings, the assessment of opsonophagocytic activity response rates and serotype-specific memory B cell immune responses to PCV antigens is required. Large population-based studies, particularly in countries where pneumococcal and Hib disease burdens remain high, should be conducted to determine if the observed effects on immune responses translate into differences in protection against disease.

BackgroundPneumococcal conjugate vaccines (PCVs) have markedly reduced childhood pneumococcal diseases, yet serotype replacement and regional heterogeneity remain important challenges. The World Health Organization recommends either a 3p + 0 or 2p + 1 schedule for PCV immunization programmes. BE-PCV14, a 14-valent vaccine, has previously been shown to be non-inferior to PCV13 in a 3p + 0 regimen. In this study, we descriptively compared the immunogenicity and safety of BE-PCV14 and PCV13 in a 2p + 1 schedule in Indian infants. MethodsIn this randomized, single-blind, multicenter trial, 400 PCV-naive infants (6-8 weeks old) were randomized 1:1 to receive either BE-PCV14 or PCV13; at 6 and 14 weeks, with a booster at 9 months. Serum IgGs against 14 vaccine serotypes plus cross-protective 6A were measured at post primary (28 days post dose 2), pre booster (at 9 months) and post booster (30 days post dose 3) time points. The primary endpoint was the proportion achieving IgG [&ge;] 0.35 {micro}g/mL (seroconversion rate) for the 12 serotypes common to both vaccines at post primary, pre booster and post booster time points. Solicited local and systemic reactions were recorded for 7 days after each dose; unsolicited, medically attended, and serious adverse events (SAEs) were captured throughout. ResultsBetween May 2023 to July 2024, 400 participants were enrolled of which 380 (95%) completed the study. Post primary seroconversion rates in the BE-PCV14 arm for common serotypes ranged from 72.6% (serotype 3) to 100% (14, 19F); PCV13 rates ranged from 71.6% to 100% (3 to 14, 19F, 19A). Post booster rates were 87.6-100% for BE-PCV14 and 85.0-100% for PCV13. BE-PCV14 elicited high responses against the two additional serotypes (22F: 96.8%; 33F: 95.3%) and cross-protective 6A (93.0%). Seroconversion rates and Geometric mean concentrations were similar between groups. Most adverse events were mild or moderate; two unrelated SAEs occurred in the BE-PCV14 arm. InterpretationAdministered in a 2p + 1 schedule, BE-PCV14 was highly immunogenic, well tolerated, and comparable to PCV13 while broadening serotype coverage, supporting its inclusion in routine infant immunisation programmes. Clinical Trials Registry of India Number: CTRI/2022/11/047366

BackgroundIt is recommended that children receive a dose of the influenza vaccine at 6 months of age and a second dose the following season. In some years, the second dose will be the same vaccine formulation, in others years it with be re-formulated to include HA proteins derived from antigenically drifted or shifted circulating influenza strains. In addition, natural exposure to influenza can create permanent changes to the memory B cell repertoire and specificities. The effect that the specificity of pre-existing humoral immunity has on antibody levels and specificity after repeat vaccination is an ongoing research area. MethodsWe used a computational framework (ssMod.v1) to simulate scenarios that occurred during the 2009 influenza pandemic: children receiving a second dose who have previously exposed to the 2009 influenza HA antigen, children previously exposed to an HA antigen antigenically similar to the 2009 influenza HA antigen, and children previously exposed to an antigenically dissimilar strain. To assess the contribution of pre-existing immunity, two experimental permutations in the sMod.v1 were made: elimination of antibody-mediated antibody clearance of vaccine (HA) antigen by pre-existing antibodies and elimination of the ability of memory B cells to form germinal centers. In the simulation, 30 days after repeat vaccination antibody specificities were examined against 12 antigenically historical vaccine/HA variant influenza strains for each of the five canonical antigenic-sites and the subdominant, conserved, stalk antigenic-site. ResultsWe found that elimination of antibody-mediated antigen clearance significantly increased antibody levels while elimination of the ability of memory B cells to form germinal center reactions significantly decreased the total antibody levels, but this was dependent on the antigenic relationship between the original vaccine and repeat vaccine and the particular antigenic-site. Moreover, highly-cross-reactive antibody was highest when the antigenic distance between original vaccine HA antigen and repeat vaccine HA antigen was larger and antibody-mediated antigen clearance was eliminated.

BackgroundEstimating attributable risk (AR) through self-controlled case series (SCCS) analyses alone may limit generalizability because SCCS only incorporate vaccinated patients with the outcome (e.g., Guillain-Barre syndrome [GBS]) who may differ from the overall population recommended for vaccination. ObjectiveWe aimed to demonstrate background event incidence rates impact on vaccine-specific GBS ARs and to standardize ARs across different vaccine studies by applying a generalizable, population-based GBS background rate for improved comparability and to better estimate the expected population-level ARs. MethodsWe identified post-licensure SCCS vaccine studies and GBS background rates using US Medicare data via targeted literature review. GBS control period rates from SCCS vaccine studies were extracted or calculated. Population-level ARs were calculated for each vaccine using published background GBS rates and the original SCCS-generated incidence rate ratios (IRRs). ResultsPublished vaccine-specific GBS IRRs ranged from 2.02 (95%CI: 0.93-4.40) for RSVPreF to 4.96 (95%CI: 1.43-17.27) for recombinant zoster vaccine (RZV). Study-specific ARs per 100,000 doses ranged from 0.28 (H1N1) to 0.90 (RSVPreF). Vaccines with lower control period GBS rates had a lower attributable risk for a given IRR. After standardization using published background GBS rates, population-level ARs were higher for vaccines with higher IRRs. For example, when using the H1N1 vaccine control period rate as the GBS background rate for AR calculation, RSVPreF had the lowest AR per 100,000 doses (0.21) and RZV the highest (2.37). ConclusionAR calculation is dependent on the control period rate within a given SCCS analysis. ARs derived exclusively from SCCS analyses may lead to incorrect conclusions regarding an adverse events absolute risk if included in product labels due to a lack of external validity. Using a representative background rate from the recommended vaccinee population, along with SCCS-derived IRR, to calculate the expected population-level AR may offer more accurate vaccine risk-benefit assessments.

BackgroundTo assist decision making on the introduction of rotavirus vaccine (RVV), pneumococcal conjugate vaccine (PCV) and human papillomavirus vaccine (HPVV), cost-effectiveness and budget impact evaluations were undertaken in Samoa, Tonga, Tuvalu and Vanuatu. MethodsA proportionate outcomes model was used to evaluate vaccine introduction in each country from a health systems perspective, using country-specific data supplemented with regional and global estimates. A 10-year vaccination program was modelled from 2021, with costs and outcomes (disability-adjusted life years; DALYs) summed over a life-time horizon and discounted at 3%. Vaccine dose costs were based on Pan American Health Organization (PAHO) Revolving Fund prices, with lower priced products also explored. FindingsIntroduction of all three vaccines in all countries could prevent over 1,000 deaths over the lifetimes of the vaccinated cohorts. The cost per DALY averted at PAHO Revolving Fund prices ranged from 43% - 73% of the per capita gross domestic product (GDP) in each country, and 15% - 58% for lower-priced vaccines. The budget impact ranged from 359% (Samoa) to 1,368% (Vanuatu) of the 2019 vaccine budgets, and 149% (Samoa) to 775% (Vanuatu) for lower-priced vaccines. Cost-effectiveness results were most sensitive to disease burden, discount rate, vaccine efficacy, and program costs. InterpretationDevelopment partner-supported introduction of HPVV, PCV and RVV may represent good value for money in Samoa, Tonga, Tuvalu and Vanuatu, depending on willingness to pay thresholds, but will place considerable burden on immunisation budgets. Financial sustainability requires increases in immunisation budgets and negotiation of affordable vaccine prices. FundingAsian Development Bank.

BackgroundVaccine hesitancy is a growing issue that the WHO ranks as one of the top 10 threats to global health. Public confidence in vaccines and rates of routine childhood vaccination have been declining around the world since the pandemic, when many countries saw the instatement of COVID-19 vaccine mandates. ObjectivesWe leveraged the COVID-19 add-on study, conducted by the CHILD Cohort Study (Canadas most phenotypically diverse, large prospective longitudinal birth cohort), to determine characteristics associated with adult participants vaccine hesitancy. Our goal was to identify potential strategies for addressing vaccine uptake concerns. This study complements others by examining more behavioural, socioeconomic, attitudinal and additional characteristics, in some cases with greater granularity, and by further exploring the effects of COVID-19 vaccine mandates on vaccine uptake and beliefs. MethodsWe generated penalized logistic regression models and used statistical tests to analyze a dataset of nearly 700 questionnaire responses where vaccine hesitancy was measured by participants agreement or disagreement with the following statements: "Getting myself vaccinated is important for the health of others in my community" and "Getting vaccinated is a good way to protect myself from disease. We also examined whether vaccination status or opinions changed after the imposition of vaccine mandates. ResultsWhile vaccine mandates were successful in increasing COVID-19 specific vaccine uptake in hesitant individuals vs confident individuals, they were ineffective in modifying hesitant individuals beliefs about vaccines. Vaccine-confident individuals were more likely to engage in pandemic safety measures such as physical distancing, while vaccine-hesitant individuals were more likely to have or had chronic medical conditions in the past, experience economic precarity, have lower socioeconomic status and/or formal education level, have had difficulty accessing medical care, and rely on friends and internet sites that were not governmental for COVID-19 related information. ConclusionsTo ensure that relevant information regarding vaccines reaches all segments of the population, outreach strategies should be tailored to individuals with a variety of cultural or educational backgrounds. Improving access to medical care could also improve access to reliable information. Vaccine mandates do not impact an individuals beliefs in vaccines, and so countering vaccine hesitancy itself is likely to be more effective in terms of ensuring continuous vaccine uptake in a population.

As vaccines have become available for COVID-19, it is important to understand factors that may impact response. The objective of this study is to describe vaccine response in a well-characterized Northern California cohort, including differences in side-effects and antibody response by vaccine type, sex, and age, as well as describe responses in subjects with pre-existing health conditions that are known risk factors for more severe COVID-19 infection. From July 2020 to March 2021, [~]5,500 adults from the East Bay Area in Northern California were followed as part of a longitudinal cohort study. Comprehensive questionnaire data and biospecimens for COVID-19 antibody testing were collected at multiple time-points. All subjects were at least 18 years of age and members of the East-Bay COVID-19 cohort who answered questionnaires related to vaccination status and side-effects at two time-points. Three vaccines, Moderna (2 doses), Pfizer-BioNTech (2 doses), and Johnson & Johnson (single dose), were examined as exposures. Additionally, pre-existing health conditions were assessed. The main outcomes of interest were anti-SARS-CoV-2 Spike antibody response (measured by S/C ratio in the Ortho VITROS assay) and self-reporting of 11 potential vaccine side effects. When comparing both doses of the Moderna vaccine to respective doses of Pfizer-BioNTech, participants receiving the Moderna vaccine had higher odds of many reported side-effects. The same was true comparing the single-dose Johnson & Johnson vaccine to dose 2 of the Pfizer-BioNTech vaccine. The antibody S/C ratio also increased with each additional side-effect after the second dose. S/C ratios after vaccination were lower in participants aged 65 and older, and higher in females. At all vaccination timepoints, Moderna vaccine recipients had a higher S/C ratio. Individuals who were fully vaccinated with Pfizer-BioNTech had a 72.4% lower S/C ratio compared to those who were fully vaccinated with Moderna. Subjects with asthma, diabetes, and cardiovascular disease all demonstrated more than a 20% decrease in S/C ratio. In support of previous findings, we show that antibody response to the Moderna vaccine is higher than the Pfizer-BioNTech vaccine. We also observed that antibody response was associated with side-effects, and participants with a history of asthma, diabetes, and cardiovascular disease had lower antibody responses. This information is important to consider as further vaccines are recommended.

BackgroundPneumococcal conjugate vaccines (PCVs) are the most expensive component of the routine immunisation schedule in Gavi-supported countries. As countries transition out of Gavi support, PCV programmes are at risk. We assessed whether immunogenicity was non-inferior after fractional doses of PCV10 (GlaxoSmithKline plc.) or PCV13 (Pfizer Inc.), when compared to full doses, and analysed vaccine serotype (VT) carriage prevalence. Methods2100 healthy infants were enrolled and randomised into seven equal-sized trial arms. Doses were delivered in the 2p+1 schedule (6, 14 weeks and 9-12 months) in six trial arms: A) Full dose PCV13, B) 40%-PCV13, C) 20%-PCV13, D) Full dose PCV10, E) 40%-PCV10, F) 20%-PCV10. Participants in the seventh trial arm received full dose PCV10 at 6, 10 and 14 weeks. Immunogenicity was assessed 4-weeks post-prime and 4-weeks post-boost. Carriage was assessed at 9 and 18 months of age. ResultsIn the per-protocol analysis, 40%-PCV13 met the non-inferiority criteria for 12/13 serotypes post-prime and 13/13 serotypes post-boost. 20%-PCV13 met the criteria for 9/13 serotypes post-prime and 10/13 serotypes post-boost. 40%-PCV10 met the criteria for 8/10 serotypes post-prime and 6/10 serotypes post-boost. 20%-PCV10 met the criteria for 7/10 serotypes post-prime and 1/10 serotype post-boost. ConclusionsA 3-dose schedule of 40%-PCV13 met the non-inferiority criteria at both timepoints and could be implemented by using 4-dose UNICEF vials as 10-dose vials. A 3-dose schedule of 40%-PCV13 would cost UNICEF 3.30 USD and represents the most affordable, effective PCV schedule option currently available for countries transitioning out of Gavi-support. ClinicalTrials.gov ID: NCT03489018.

BackgroundHigh-dose inactivated influenza vaccination (HD-IIV) demonstrates superior effectiveness versus standard-dose vaccination (SD-IIV) in adults aged [&ge;]60 years. A recent meta-analysis integrated complementary evidence sources of representing over 85 million individuals across 14 influenza seasons. MethodsA previously developed model was updated using life-time horizon and societal perspective. Updated parameters included demographics, costs, hospitalization rates, and relative vaccine effectiveness (rVE): RCT evidence (24% for ILI, 7% for cardiorespiratory hospitalizations) and RCT + real-world evidence (RWE) (15% for ILI, 8% for cardiorespiratory hospitalizations). ResultsHD-IIV resulted in incremental cost-effectiveness ratios of {euro}7,300/QALY (RCT evidence) and {euro}5,800/QALY (RCT+RWE evidence). Implementation would prevent 7,200 general practitioner visits, 6,300 cardiorespiratory hospitalizations, and 269 deaths, by using RCT evidence. Probabilistic sensitivity analysis demonstrated >99% probability of cost-effectiveness at {euro}20,000/QALY threshold for both RCT and RCT+RWE evidence. ConclusionsHD-IIV remains highly cost-effective for Dutch adults aged [&ge;]60 years under updated evidence scenarios, supporting implementation in the national immunization programme. HighlightsO_LIThe economic analysis of high-dose inactivated influenza vaccine was updated. C_LIO_LIRelative vaccine effectiveness of HD-IIV incorporating recent evidence was used. C_LIO_LIHD-IIV remains cost-effective in Dutch adults aged [&ge;]60. C_LI

BackgroundVaccination helps prevent SARS-CoV-2 infection and severe COVID-19. However, vaccine-induced humoral immune responses vary among individuals and wane over time. We aimed to describe the SARS-CoV-2 anti-spike IgG antibody response to vaccination and identify health and demographic factors associated with this response among children and adults. MethodsWe studied a subset of double-vaccinated children (n= 151; mean age: 12 {+/-}1.5 years, 46% female) and adults (n= 995; 44 {+/-}6.0 years, 60% female) from the Canadian CHILD Cohort. Dried blood spots were collected over two time periods (March 2021 to September 2021; October 2021 to January 2022). Antibody levels were quantified using automated chemiluminescent ELISAs. Demographic, vaccination, and health data were collected via online questionnaires. Associations were determined using multivariable regression. ResultsOur cohort had SARS-CoV-2 anti-spike seropositivity rate of 97% following two COVID-19 vaccine doses. In both children and adults, the highest antibody levels were observed around three months post-vaccination and did not differ by biological sex. Higher antibody levels were associated with: prior SARS-CoV-2 infection ({beta}=0.15 scaled luminescence units, 95%CI, 0.06-0.24), age <18 years ({beta}=0.15, 95%CI 0.05-0.26) and receiving the Moderna mRNA ({beta}=0.23, 95%CI 0.11-0.34) or Pfizer-BioNTech mRNA vaccines ({beta}= 0.10, 95%CI, 0.02-0.18) vs. a combination of mRNA and Oxford-AstraZeneca viral vector vaccines. There were no differences in antibody levels when comparing a 3-8 vs. 9-16-week interval between vaccine doses. InterpretationWe identified key factors associated with post-vaccination antibody responses in children and adults, which could help improve future vaccine development and deployment among different population subgroups.

Two live attenuated vaccines (LAVs), LMA and LMP, were evaluated alone or in combination with a trivalent adenoviral vector-based vaccine (Ad5-YFV) for their efficacy and immune responses in wild type (WT) and interferon gamma (IFN{gamma}) knockout (KO) mice in a C57BL/6 background. While LMA and LMP are triple deletion mutants of Yersinia pestis CO92 strain, Ad5-YFV incorporates three protective plague immunogens. An impressive 80-100% protection was observed in all vaccinated animals against highly lethal intranasal challenge doses of parental Y. pestis CO92. All vaccinated mice generated robust humoral and cellular immune responses. The immunized WT mice showed overall better antibody responses in both serum and bronchoalveolar lavage fluid with much higher percentages of polyfunctional T cell populations. On the other hand, vaccinated IFN{gamma} KO mice displayed better B cell activity in germinal centers with higher percentages of activated antigen specific T cells and memory T cells. In addition, depletion of IFN{gamma} and tumor necrosis factor alpha (TNF) from immunized WT mice prior to and during infection did not reduce protection against pulmonary Y. pestis CO92 challenge. These data demonstrated a dispensable nature of IFN{gamma} in mediating protection by the aforementioned vaccines. This is the first detailed immunogenicity study of two plague LAVs administered either alone or in combination with an Ad5-YFV vaccine in a prime-boost immunization strategy in IFN{gamma} KO mice. Further, by combining advantages of live-attenuated and adenovirus-based vaccines, augmentation of generalized immune responses were observed which could be beneficial in providing long-lasting immunity in the host.

In this work we evaluated recombinant receptor binding domain (RBD) based vaccine formulation prototypes with potential for further clinical development. We assessed different formulations containing RBD plus Alum, AddaS03, AddaVax or the combination of Alum and U-Omp19: a novel Brucella spp. protease inhibitor vaccine adjuvant. Results show that the vaccine formulation composed of U-Omp19 and Alum as adjuvants have a better performance: it significantly increased mucosal and systemic neutralizing antibodies in comparison to antigen plus Alum, AddaVax or AddaS03. Antibodies induced with the formulation containing U-Omp19 not only increased their neutralization capacity against the wild-type virus but also cross neutralized alpha, lambda and gamma variants with similar potency. Also, addition of U-Omp19 to vaccine formulation increased the frequency of RBD-specific geminal center B cells and plasmablasts. Additionally, U-Omp19+Alum formulation induced RBD-specific Th1 and CD8+ T cell responses in spleens and lungs. Finally, this vaccine formulation conferred protection against an intranasal SARS-CoV-2 challenge of K18-hACE2 mice.

BackgroundOlder adults face a disproportionately high risk of severe influenza, yet the standard inactivated vaccine (IIV) offers suboptimal protection in this population. This study evaluates the cost-effectiveness of replacing IIV with the recombinant influenza vaccine (RIV) for adults aged [&ge;]50, [&ge;]65, and [&ge;]80 years in Hong Kong. MethodsA decision tree model was used to compare RIV with IIV for adults aged [&ge;]50, [&ge;]65, and [&ge;]80 years in Hong Kong, from a societal perspective. Costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) were evaluated with the impact of parameter uncertainty on the results assessed via deterministic and probabilistic sensitivity analyses. ResultsFor adults [&ge;]50 years, RIV increased total costs by USD5.1 (HKD39.8) per person and gained 0.00012 QALYs (ICER: USD40,659 [HKD317,140] per QALY) compared to IIV. Among adults [&ge;]65 years, RIV cost USD6.0 (HKD46.8) more and gained 0.00021 QALYs (ICER: USD29,077 [HKD226,801] per QALY). For adults [&ge;]80 years, RIV cost USD3.2 (HKD25.0) more and gained 0.00015 QALYs (ICER: USD21,092 [HKD164,518] per QALY). ICERs were less than willingness-to-pay thresholds of one to three times Hong Kongs gross domestic product per capita. ConclusionsRIV is cost-effective compared with IIV for adults [&ge;]50, [&ge;]65, and [&ge;]80 years in Hong Kong, with the lowest ICER observed in individuals [&ge;]80 years.