A case-control study of risk factors for intussusception among infants in eastern France after the introduction of the rotavirus vaccine

ObjectiveThe objective of the present study was to investigate the risk factors for intussusception (IS) among infants, including vaccination against rotavirus.MethodsCase-control study with systematic inclusion of all infants aged <1 year with suspected IS admitted to emergency departments in the eastern region of France between 1 April 2008 and 31 March 2012. All cases classed level 1 according to the Brighton classification were matched to 4 hospital controls. Two exposure windows were examined; exposure to the first dose of rotavirus vaccine in the 7 and in the 14 days prior to the occurrence of IS.ResultsA total of 115 cases were matched with 457 controls. The average vaccination coverage rate over the 4 years of study was 8.6%. Rotavirus vaccine was not found to be significantly associated with the occurrence of IS in the 7 days (odds ratio (OR) not calculated; p = 0.99) and in the 14 days after administration of one dose vaccine (OR 1.33, 95% confidence interval (CI) 0.14–12.82). Infant formula alone or combined with breastfeeding was associated with an excess risk of IS (OR 2.74, 95% CI 1.10–6.79). A history of gastroenteritis within 2 weeks prior to hospitalisation was also associated with an increased risk (OR 2.24, 95% CI 1.07–4.67).ConclusionOur study indicates that infant formula alone or combined with breastfeeding is a risk factor for IS. A small, non-significant increase in the risk of IS was observed after rotavirus vaccination, although the low vaccine coverage rate likely precluded detection of a significant increase in risk.     

Impact of rotavirus vaccine on paediatric rotavirus hospitalisation and intussusception in New Zealand: A retrospective cohort study

BackgroundRotavirus results in a significant burden of hospitalisations and deaths globally. Rotavirus vaccine has been used in New Zealand since July 2014. The aim of this study was to assess the safety and effectiveness of RotaTeq® vaccine in New Zealand between 2006 and 2016.MethodsA national cohort study of 723,695 children aged less than 6 years was carried out using linked administrative datasets. Study outcomes were hospitalisation for intussusception, rotavirus, and all-cause gastroenteritis. Intussusception hospitalisation rates were calculated from 2006 to 2016, and rotavirus and all-cause gastroenteritis hospitalisation rates from 2011 to 2016. We examined the effect of RotaTeq® vaccination on rotavirus and all-cause gastroenteritis hospitalisation rates using Poisson regression. Adjusted incidence rate ratios controlled for sex, year of birth, ethnicity, socioeconomic deprivation, and district health board area.ResultsSignificant reductions in the incidence of rotavirus hospitalisation were seen in all age groups, ethnicities, and deprivation following the introduction of RotaTeq®. There was a 92.6% reduction in hospitalisation incidence in the vaccinated cohort (p < 0.0001). There was also a 48% reduction in all-cause gastroenteritis hospitalisation incidence in the vaccinated cohort (p < 0.0001). The average annual intussusception rate in children aged less than 3 years was 26.2 per 100,000, with no significant change over time (p = 0.847).ConclusionsIn New Zealand the introduction of RotaTeq® resulted in a significant reduction in rotavirus hospitalisation, and a halving in all-cause gastroenteritis hospitalisation. There has been no change in the overall incidence of intussusception or clear change in patterns of cases, although intussusception cases did occur within risk period immediately post vaccine.     

Long-term effectiveness of pentavalent and monovalent rotavirus vaccines against hospitalization in Taiwan children

BackgroundTwo rotavirus vaccines (RV1 and RV5) are available on the private market in Taiwan, not included in national immunization program. Scanty reports evaluated the rotavirus vaccine effectiveness (VE) in Asian countries.MethodsFrom February 2014-July 2017, we conducted a prospective case-control study in ten hospitals in Taiwan. Case-patients included children aged 8–59 months, and hospitalized with laboratory-confirmed rotavirus acute gastroenteritis (AGE). For each case patient, up to four controls, rotavirus-negative AGE or non-AGE illnesses, respectively, were matched by gender, age and enrolled date. Vaccination history was confirmed through vaccination card or hospital record. VE was calculated as (1 − odds ratio of vaccination) × 100%.ResultsTotally 4248 AGE patients and 2242 non-AGE controls were enrolled. A total of 330 case-patients with rotavirus AGE, 1226 rotavirus-negative AGE controls and 1122 non-AGE controls were included for analysis. Unvaccinated rate was 85.15% for rotavirus-positive cases, 42.9% for rotavirus-negative controls, and 34.31% for non-AGE controls. VE of two-dose RV1 was 84.9% (95% confidence interval [CI]:77.7%, 90.1%) for rotavirus-negative AGE and 88.9% (95% CI: 83.4%, 92.8%) for non-AGE controls, while VE of three-dose RV5 was 92.5% (95% CI: 85.1%, 96.7%) and 96.4% (95% CI: 91.9%, 98.6%), respectively. For respective vaccine, VEs were not significantly different in term of rotavirus genotypes. VEs of both vaccines declined <80% in children aged three years by combined controls.ConclusionsBoth vaccines provided excellent and sustained protection against rotavirus AGE hospitalization in children in Taiwan, but the effectiveness declined slightly in children aged three years.     

Effects of rotavirus vaccine on all-cause acute gastroenteritis and rotavirus hospitalizations in Israel: A nationwide analysis

BackgroundIn December 2010, the pentavalent rotavirus vaccine (RotaTeq) was added to the national immunization program in Israel. The study aim was to examine national reductions in all-cause acute gastroenteritis (AGE) and rotavirus gastroenteritis (RVGE) hospitalizations among children aged 0–59 months following the introduction of universal rotavirus immunization in Israel.MethodsWe extracted data from the Israel National Hospital Discharge Database. Hospitalization rates were calculated by dividing the annual number of all-cause AGE and RVGE hospitalizations by the number of children aged 0–59 months residing Israel. To assess rate reductions, we compared the mean hospitalization rate for the pre-vaccine years (2002–2008) with that for the universal vaccination years (2011–2017). Interrupted time-series analyses were undertaken. During 2008–2010 rotavirus vaccines were partially available.ResultsA total of 131,116 AGE hospitalizations were reported, of which 13,111 (10.0%) were coded as RVGE hospitalizations. The average annual all-cause AGE hospitalization rate during the pre-vaccine period was 147.9 (95% CI 146.7–149.0) per 10,000 children aged 0–59 months, and declined by 38.7–53.0% during the universal vaccination years. The average annual pre-vaccine RVGE hospitalization rate was 16.9 (95% CI 16.5–17.3) per 10,000 children, and declined by 89.1% during 2016–2017.Findings from interrupted time-series analyses showed significant impact of introducing universal rotavirus immunization on the declines of all-cause AGE and RVGE hospitalizations rates. A multivariable Autoregressive Integrated Moving Average model showed that the variable “immunization period” was a significant predictor of RVGE hospitalizations (t = 7.3, p < 0.001) for the universal vaccination years.The declines in hospitalizations rates of all-cause AGE were lower among Arab children compared to Jewish children, but the declines in RVGE rates were similar between the groups.ConclusionsNational hospitalization data demonstrated substantial and consistent reductions in all-cause AGE and RVGE hospitalizations following the implementation of universal rotavirus vaccination program.     

Aiming too high: Shoulder injury related to vaccine administration (SIRVA): A case series

PurposeShoulder injury directly related to vaccination (SIRVA) occurs when a vaccine is administered too high in the shoulder. The primary aim of this study was to accurately detail the occurrence, symptoms, diagnosis, management and long-term outcomes of SIRVA cases in Victoria, Australia.Principal resultsThe study identified 102 SIRVA cases from 2007 to 2020 from the Surveillance of Adverse Events Following Vaccination in the Community (SAEFVIC) database. The majority [73/85; (86 %)] of cases resolved completely with a median time to resolution of 8 weeks and no statistically significant difference in recovery by immunisation provider type or baseline imaging.Major conclusionsThis large case series includes long-term clinical progress in SIRVA, allowing accurate evaluation and analysis. Further evaluation is required to establish if other risk factors contribute to SIRVA, which may help with targeted, tailored education for providers on correct vaccine administration technique, including in large and rapid vaccine rollouts.     

Concomitant administration of a liquid formulation of human rotavirus vaccine (porcine circovirus-free) with routine childhood vaccines in infants in the United States: Results from a phase 3, randomized trial

BackgroundIn response to the detection of porcine circovirus type 1 (PCV-1) in the human rotavirus vaccine (HRV), a PCV-free HRV (no detection of PCV-1 and PCV-2 according to the detection limit of tests used) was developed. Liquid (Liq) PCV-free HRV previously showed immunogenicity and safety profiles comparable to lyophilized (Lyo) HRV.MethodsThis was a phase 3a, randomized, single-blind study (NCT03207750) conducted in the United States. Healthy infants aged 6–12 weeks received 2 doses (0, 2 months) of either Liq PCV-free HRV or Lyo HRV with routine vaccines (0, 2, 4 months): diphtheria-tetanus-acellular pertussis, hepatitis B and inactivated poliovirus combination vaccine (DTaP-HBV-IPV), monovalent tetanus toxoid-conjugated vaccine against Haemophilus influenzae type b (Hib-TT), and 13-valent pneumococcal conjugate vaccine. Co-primary objectives were: (i) to assess non-inferiority of immune responses to routine vaccine antigens 1 month post-dose 3 following co-administration with Liq PCV-free HRV compared to Lyo HRV; (ii) to rule out a 10% decrease in seroresponse to pertussis antigens after dose 3. Other objectives were to evaluate immunogenicity and safety of HRV vaccines.ResultsOf 1272 vaccinated infants, 990 (489 in Liq PCV-free HRV and 501 in Lyo HRV group) were included in the per-protocol set. All statistical criteria were met, thus co-primary objectives were demonstrated. Seroprotection/seropositivity rates in both groups were high: 100% for diphtheria/tetanus, ≥99.3% for HBV, ≥99.8% for polio, ≥99.8% for each pertussis antigen, ≥90.8% for all pneumococcal serotypes except serotype 3 (≥69.1%), and ≥ 97.4% for Hib. Most infants seroconverted for anti-RV antibodies (76.3% of Liq PCV-free HRV and 78.9% of Lyo HRV recipients). Geometric mean concentrations/titers were comparable between groups. Incidences of adverse events and serious adverse events were similar between groups.ConclusionRoutine pediatric vaccines co-administered with Liq PCV-free HRV showed non-inferior immune responses and similar safety profiles to those following co-administration with Lyo HRV.     

Economic evaluation of the introduction of rotavirus vaccine in Hong Kong

BackgroundRotavirus is a common cause of severe gastroenteritis in young children in Hong Kong (HK) with a high economic burden. This study aimed to evaluate the cost-effectiveness of introducing rotavirus vaccination into the HK Government’s Childhood Immunisation Programme (CIP) and to include the potential protective effect of the vaccine against seizures.MethodsA decision-support model was customised to estimate the potential impact, cost-effectiveness and benefit-risk of rotavirus vaccination in children below 5 years over the period 2020–2029 in HK. Two doses of Rotarix® and three doses of RotaTeq® were each compared to no vaccination. Rotavirus treatment costs were calculated from a governmental health sector perspective (i.e., costs of public sector treatment) and an overall health sector perspective (both governmental and patient, i.e., costs of public sector treatment, private sector treatment, transport and diapers). We ran probabilistic and deterministic uncertainty analyses.ResultsIntroduction of rotavirus vaccination in HK could prevent 49,000 (95% uncertainty interval: ~44,000–54,000) hospitalisations of rotavirus gastroenteritis and seizures and result in ~50 (95% uncertainty interval: ~25–85) intussusception hospitalisations, over the period 2020–2029 (a benefit-risk ratio of ~1000:1), compared to a scenario with no public or private sector vaccine use. The discounted vaccination cost would be US$51–57 million over the period 2020–2029 based on per-course prices of US$72 (Rotarix®) or US$78 (RotaTeq®), but this would be offset by discounted treatment cost savings of US$70 million (government) and US$127 million (governmental and patient health sector). There was a greater than 94% probability that the vaccine could be cost-saving irrespective of the vaccine product or perspective considered. All deterministic ‘what-if’ scenarios were cost-saving from an overall health sector perspective (governmental and patient).ConclusionsRotavirus vaccination is likely to be cost-saving and have a favourable benefit-risk profile in HK. Based on the assumptions made, our analysis supports its introduction into CIP.     

Immunogenicity of the pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) administered concomitantly with the meningococcal serogroup B (4CMenB) vaccine in infants: A post-hoc analysis in a phase 3b,randomised, controlled trial

BackgroundNo data are currently available on immunogenicity of higher-valent pneumococcal conjugate vaccines when co-administered with a 4-component meningococcal serogroup B vaccine (4CMenB).MethodsPost-hoc analysis of pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) immunogenicity when co-administered with 4CMenB (2 + 1 schedule) and/or a CRM-conjugated meningococcal serogroup C vaccine (MenC-CRM) in a trial assessing 4CMenB reduced schedules and co-administration with MenC-CRM (NCT01339923). Infants were randomized to receive 4CMenB and MenC-CRM (Group 1) or MenC-CRM (Group 2) at 3, 5, and 12 months (M) of age. Both groups received PHiD-CV (3 + 1 schedule) as part of the Brazilian national immunisation programme at 3 M, 5 M, 7 M, and 12 M of age. Antibody responses were assessed pre-vaccination, 1 M post-dose 2, pre-booster, and 1 M post-booster.ResultsAnti-pneumococcal antibody responses were in similar ranges in the two study groups.Conclusions4CMenB co-administration did not seem to impact antibody responses to PHiD-CV in infants.     

Explaining the formation of a plateau in rotavirus vaccine impact on rotavirus hospitalisations in Belgium

BackgroundObservational data on the reduction in hospitalisations after rotavirus vaccine introduction in Belgium suggest that vaccine impact plateaued at an unexpectedly high residual hospitalisation rate. The objective of this analysis was to identify factors that influence real-world vaccine impact.MethodsData were collected on hospitalisations in children aged ≤ 5 years with rotavirus disease from 11 hospitals since 2005 (the RotaBIS study). The universal rotavirus vaccination campaign started late in 2006. A mathematical model simulated rotavirus hospitalisations in different age groups using vaccine efficacy and herd effect, influenced by vaccine coverage, vaccine waning, and secondary infection sources. The model used optimisation analysis to fit the simulated curve to the observed data, applying Solver add-in software. It also simulated an ‘ideal’ vaccine introduction maximising hospitalisation reduction (maximum coverage, maximum herd effect, no waning), and compared this with the best-fit simulated curve. Modifying model input values identified factors with the largest impact on hospitalisations.ResultsCompared with the ‘ideal’ simulation, observed data showed a slower decline in hospitalisations and levelled off after three years at a higher residual hospitalisation rate. The slower initial decline was explained by the herd effect in unvaccinated children. The higher residual hospitalisation rate was explained by starting the vaccine programme in November, near the rotavirus seasonal peak. This resulted in low accumulated vaccine coverage during the first rotavirus disease peak season, with the consequential appearance of secondary infection sources. This in turn reduced the herd effect, resulting in a diminished net impact.ConclusionsOur results indicate that countries wishing to maximise the impact of rotavirus vaccination should start vaccinating well ahead of the rotavirus seasonal disease peak. This maximises herd effect during the first year leading to rapid and high reduction in hospitalisations. Secondary infection sources explain the observed data in Belgium better than vaccine waning.     

Vaccination rates and adherence in premature infants before and after pneumococcal conjugate vaccine schedule change for term infants – A claims database analysis in Germany

BackgroundIn 2015, the German Standing Committee on Vaccination (STIKO) changed the pneumococcal conjugate vaccination (PCV) schedule for mature infants from a 3+1 scheme (2, 3, 4, and 11–14 months of age) to a 2+1 scheme (2, 4, and 11–14 months of age). For premature infants, the 3+1 scheme remained. The aim of this study was to assess vaccination rates, completeness, and timeliness for PCV in premature infants before and after the modified recommendation.MethodsA retrospective claims data analysis using the “Institut für angewandte Gesundheitsforschung Berlin” Research Database was conducted. Premature infants born in 2013 and 2016 with an individual follow-up of 24 months were included. Hexavalent combination (HEXA) vaccination with a consistent 3+1 recommendation for mature and premature infants was analyzed as reference vaccination.ResultsAfter 24 months, the PCV rate for at least one dose remained stable in premature newborns of 2016 compared to 2013, while the HEXA vaccination rate increased slightly. However, a significant decrease of a completed PCV schedule (4 doses) in premature infants was noted, whereas the completeness of HEXA vaccination did not change. The timeliness of PCV in premature newborns increased for the first and the booster PCV, while the timeliness of HEXA immunization did not change from 2013 to 2016.ConclusionAlthough STIKO still recommends a 3+1 PCV schedule for premature infants in Germany, premature infants were vaccinated according to the changed recommendations for mature born infants. A substantial share of premature infants remained unvaccinated, and their vaccinations were often delayed.     

Cost-effectiveness analysis of the implementation of a National Immunization Program for rotavirus vaccination in a country with a low rotavirus gastroenteritis-related mortality: A South Korean study

Rotavirus is a leading cause of severe gastroenteritis among children younger than 5 years in South Korea. Two rotavirus vaccines (RVs), pentavalent human-bovine reassortant vaccine (Rotateq®; RV5) and attenuated human strain originated monovalent vaccine (Rotarix®; RV1), have been available for voluntary vaccination using out-of-pocket payment since 2007 and 2008, respectively. Yet, RVs are not included in the National Immunization Program (NIP), partly because of the low associated mortality rate. We assessed the cost-effectiveness of RVs to assist the evidence-based decision-making process for NIP implementation in South Korea. Using a transparent age-structured static cohort model, we simulated the experience of ten annual birth cohorts of South Korean children from 2018 to 2027. Model inputs included rotavirus gastroenteritis (RVGE) incidence and mortality rates, RVGE treatment costs, vaccine coverage and timeliness, and vaccine effectiveness and price. The incremental costs of including RVs in the NIP compared to no vaccination were 59,662,738 USD and 152,444,379 USD for RV1 and RV5, respectively. The introduction of RV1 and RV5 can prevent 4799 disability-adjusted life years (DALYs) and 5068 DALYs. From the societal perspective, the incremental cost-effectiveness ratios (ICERs) for adopting RV into the NIP versus no vaccination were 12,432 USD per DALY averted for RV1 and 30,081 USD per DALY averted for RV 5. The weighted average for the ICERs of the two vaccines computed using the market share of each vaccine in the current voluntary use as a weight, was 21,698 USD per DALY averted. The estimated ICER was below 1 × gross domestic product per capita (30,000 USD), which has been a commonly used willingness-to-pay threshold for health care technology assessment in South Korea, suggesting that introducing RVs into the NIP would be cost-effective.     

Timeliness and factors associated with rotavirus vaccine uptake among Australian Aboriginal and non-Aboriginal children: A record linkage cohort study

ObjectivesRotavirus vaccines (RV), included in Australia’s National Immunisation Program from mid-July 2007, are unique in strict time limits for administration. Here, we report on timeliness of RV uptake, compare cumulative RV coverage to age 12 months with DTPa, and assess factors associated with receipt of RV among Aboriginal and non-Aboriginal children.MethodsBirth records for 681,456 children born in two Australian states in 2007–2012 were probabilistically linked to national immunisation records. We assessed on-time coverage (defined as receipt of vaccine dose between 4 days prior to scheduled date and the recommended upper limit) for RV and compared this to diphtheria-tetanus-pertussis (DTPa) vaccine. Logistic regression modelling was used to assess independent determinants of receipt of RV.ResultsCompared to non-Aboriginal infants, on-time RV coverage was lower for all doses among Aboriginal infants. Post the upper age limit of RV dose2, DTPa dose2 coverage increased by 9–16% to ≥90%, whereas RV coverage remained around 77% (Aboriginal) and 85% (non-Aboriginal). Compared to first-born children, the adjusted odds of receiving ≥1 RV dose if born to a mother with ≥3 previous births was 0.30 (95%CI: 0.27–0.34) among Aboriginal, and 0.53 (95%CI: 0.51–0.55) among non-Aboriginal children. Prematurity (<33 weeks), low birthweight (<1500 g), maternal age <20 years, maternal smoking during pregnancy and living in a disadvantaged area were independently associated with decreased vaccine uptake.ConclusionsAboriginal children are at greater risk of rotavirus disease than non-Aboriginal children and delayed vaccine receipt is substantially higher. Although specific programs targeting groups at risk of delayed vaccination might improve RV coverage, relaxation of upper age restrictions is most readily implementable, and its overall risk-benefit should be evaluated.     

Safety and immunogenicity of 15-valent pneumococcal conjugate vaccine in Japanese healthy infants: A phase III study (V114-033)

BackgroundThis phase III study evaluated safety, tolerability, and immunogenicity of V114 (15-valent pneumococcal conjugate vaccine) in Japanese infants. V114 contains all 13 serotypes in PCV13 plus additional serotypes 22F and 33F.MethodsHealthy Japanese infants were randomized to receive three primary doses of V114 or PCV13 (dose 1 at 2–6 months of age; doses 2 and 3 ≥ 27 days after prior dose), plus a toddler dose at 12–15 months of age. Adverse events (AEs) were collected on Days 1–14 following each vaccination. Serotype-specific anti-pneumococcal immunoglobulin G (IgG) was measured 30 days post-dose 3, pre-dose 4, and 30 days post-dose 4. Primary objectives included non-inferiority of V114 to PCV13 for the 13 shared serotypes based on serotype-specific IgG response rates (IgG ≥ 0.35 μg/mL) and geometric mean concentration (GMC) ratios, and for serotypes 22F and 33F based on IgG response rates and compared with the lowest response of any serotype in the PCV13 group, at 30 days post-dose 3.ResultsOverall, 694 infants were randomized to V114 (n = 347) or PCV13 (n = 347). Proportions of participants with solicited and serious AEs were comparable between vaccination groups. V114 met non-inferiority criteria for all 13 shared serotypes, based on difference in proportion of responders (lower bound of two-sided 95 % confidence interval [CI] > −10.0) and IgG GMC ratios (V114/PCV13, lower bound of two-sided 95 % CI > 0.5) at 30 days post-dose 3. The non-inferiority criterion based on IgG response rates was met for serotype 22F, but narrowly missed for serotype 33F (90.9 %, lower bound of two-sided 95 % CI −10.6).ConclusionIn Japanese infants, a four-dose series of V114 was generally well tolerated. Compared with PCV13, V114 provided non-inferior immune responses to the 13 shared serotypes and higher immune responses to serotype 22F and 33F post-primary series.Trial registration: ClinicalTrials.gov: NCT04384107; EudraCT 2019-003644-68.     

Comparison of immunogenicity between candidate influenza A(H3N2) virus vaccine strains in Japan: A randomized controlled trial using a monovalent vaccine of A/Saitama/103/2014 (CEXP-002) and A/Hong Kong/4801/2014 (X-263)

BackgroundFor the 2017–18 influenza season, A/Saitama/103/2014 (CEXP-002) (Saitama strain) was antigenically more similar to prior circulating strains than A/Hong Kong/4801/2014 (X-263) (Hong Kong strain) in a ferret model and was selected as the A(H3N2) vaccine virus strain in Japan. However, the Saitama strain grew poorly, and the Japanese government switched to the Hong Kong strain, raising public concerns of poor effectiveness. To enhance understanding of the correlation between antigenicity in experimental models and immunogenicity, as a surrogate measure of vaccine effectiveness, in the human population, we compared the immunogenicity of specially-prepared single dose monovalent influenza A(H3N2) vaccines containing the Saitama or the Hong Kong strain.MethodsA randomized controlled trial of 100 healthy adults aged 20–64 years (n = 50/group) was conducted. Virus neutralization assay was performed on sera from days 0 (pre-vaccination) and 21 (post-vaccination). Geometric mean titer (GMT), mean fold rise (MFR), seroconversion proportion (SCP), and seroprotection proportion (SPP) were calculated for vaccine strains and a representative circulating A(H3N2) virus strain (A/Osaka/188/2017).ResultsFor the Hong Kong strain, post-vaccination GMT was significantly higher in the Hong Kong vaccine recipients (1:546 vs 1:260, p < 0.01), but MFR, SCP, and SPP were similar for both vaccine groups. For the Saitama strain, post-vaccination GMT (1:116 vs 1:61, p = 0.01) and SPP (86% vs 68%, p = 0.03) were significantly higher in the Hong Kong vaccine recipients, but MFR and SCP were similar for both vaccine groups. Against A/Osaka/188/2017, post-vaccination GMT and MFR were similar in both vaccine groups, but SCP (32% vs 4%, p < 0.01) and SPP (28% vs. 6%, p < 0.01) were significantly higher in the Hong Kong vaccine recipients.ConclusionThe Hong Kong vaccine induced better or equivalent immunogenicity in comparison to the Saitama vaccine. Our trial showed that antigenic similarity in experimental models does not necessarily correlate with immunogenicity in the human population.Clinical trial registration: UMIN000029293.     

Evaluation of non-specific effects of human rotavirus vaccination in medical risk infants

BackgroundThe WHO recommends research into non-specific effects of vaccination. For rotavirus vaccines, these have not yet been well established. We studied non-specific effects up to 18 months of age using data from a quasi-experimental before-after study comparing cohorts of rotavirus vaccinated and unvaccinated infants with medical risk conditions.MethodsInfants were enrolled at six weeks of age before and after a stepped-wedge implementation of a hospital-based risk-group rotavirus vaccination program. Other infant vaccinations were administered according to the Dutch National Immunization Program and similar in both cohorts. Non-specific effect outcomes were prospectively collected using monthly questionnaires and included acute hospitalization (excluding for acute gastroenteritis), monthly incidence of acute respiratory illness and eczema. We used time-to-event analysis and negative binomial regression to assess the effect of at least one dose of rotavirus vaccination for each of these outcomes.FindingsThe analysis included 496 rotavirus unvaccinated and 719 vaccinated medical risk infants. In total, 1067 (88%) were premature, 373 (31%) small for gestational age and 201 (17%) had a congenital pathology. The adjusted hazard ratio for first acute hospitalization was 0·91 (95 %CI 0·76;1·16) for rotavirus vaccinated versus unvaccinated infants. Adjusted incidence rate ratio for acute respiratory illness was 1·05 (95 %CI 0·96;1·15) and for eczema 0·89 (95 %CI 0·69;1·15).ConclusionThe results suggest no, or minimal non-specific effects from rotavirus vaccination on acute hospitalization, acute respiratory illness or eczema in medical risk infants.Trial registration: as NTR5361 in the Dutch trial registry, www.trialregister.nl.     

Immunogenicity and safety of a single booster dose of NVX-CoV2373 (TAK-019) in healthy Japanese adults who had previously received a primary series of COVID-19 mRNA vaccine: Primary analysis report of a phase 3 open-label trial

BackgroundWe evaluated the immunogenicity and safety of a booster dose of NVX-CoV2373 in Japanese adults who had completed a primary series of COVID-19 mRNA vaccine 6–12 months previously.MethodsThis single-arm, open-label, phase 3 study, conducted at two Japanese centres, enrolled healthy adults ≥ 20 years old. Participants received a booster dose of NVX-CoV2373. The primary immunogenicity endpoint was non-inferiority (lower limit of the 95 % confidence interval [CI] ≥ 0.67) of the geometric mean titre (GMT) ratio of titres of serum neutralizing antibodies (nAbs) against the SARS-CoV-2 ancestral strain 14 days after booster vaccination (day 15) in this study, compared with those 14 days after the second primary NVX-CoV2373 vaccination (day 36) in the TAK-019-1501 study (NCT04712110). Primary safety endpoints included local and systemic solicited adverse events (AEs) up to day 7 and unsolicited AEs up to day 28.ResultsBetween 15 April 2022 and 10 May 2022, 155 participants were screened and 150, stratified by age (20–64 years old [n = 135] or ≥ 65 years old [n = 15]), received an NVX-CoV2373 booster dose. The GMT ratio between titres of serum nAbs against the SARS-CoV-2 ancestral strain on day 15 in this study and those on day 36 in the TAK-019-1501 study was 1.18 (95 % CI, 0.95–1.47), meeting the non-inferiority criterion. Following vaccination, the proportion of participants who reported local and systemic solicited AEs up to day 7 was 74.0 % and 48.0 %, respectively. The most common local and systemic solicited AEs were tenderness (102 participants [68.0 %]) and malaise (39 participants [26.0 %]), respectively. Seven participants (4.7 %) reported unsolicited AEs between vaccination and day 28; all were severity grade ≤ 2.DiscussionA single heterologous NVX-CoV2373 booster induced rapid and robust anti-SARS-CoV-2 immune responses, addressing waning immunity in healthy Japanese adults, and had an acceptable safety profile.ClinicalTrials.gov identifier: NCT05299359.     

Safety,tolerability, and immunogenicity of V114 pneumococcal vaccine compared with PCV13 in a 2+1 regimen in healthy infants: A phase III study (PNEU-PED-EU-2)

BackgroundThis phase III study evaluated safety, tolerability, and immunogenicity of V114 (15-valent pneumococcal conjugate vaccine) in healthy infants. V114 contains all 13 serotypes in PCV13 and additional serotypes 22F and 33F.MethodsHealthy infants were randomized to two primary doses and one toddler dose (2+1 regimen) of V114 or PCV13 at 3, 5, and 12 months of age; diphtheria, tetanus, pertussis (DTaP), inactivated poliovirus (IPV), Haemophilus influenzae type b (Hib), hepatitis B (HepB) vaccine was administered concomitantly. Adverse events (AEs) were collected on Days 1–14 following each vaccination. Serotype-specific anti-pneumococcal immunoglobulin G (IgG) was measured 30 days post-primary series, immediately prior to toddler dose, and 30 days post-toddler dose. Primary objectives included non-inferiority of V114 to PCV13 for 13 shared serotypes and superiority of V114 to PCV13 for serotypes 22F and 33F.Results1191 healthy infants were randomized to V114 (n = 595) or PCV13 (n = 596). Proportions of participants with solicited AEs and serious AEs were comparable between groups. V114 met non-inferiority criteria for 13 shared serotypes, based on difference in proportions with serotype-specific IgG ≥0.35 μg/mL (lower bound of two-sided 95% confidence interval [CI] >−10.0) and IgG geometric mean concentration (GMC) ratios (lower bound of two-sided 95% CI >0.5) at 30 days post-toddler dose. V114 met superiority criteria for serotypes 22F and 33F, based on response rates (lower bound of two-sided 95% CI >10.0) and IgG GMC ratios (lower bound of two-sided 95% CI >2.0) at 30 days post-toddler dose.Antibody responses to DTaP-IPV-Hib-HepB met non-inferiority criteria, based on antigen-specific response rates.ConclusionA two-dose primary series plus toddler dose of V114 was well-tolerated in healthy infants. Compared with PCV13, V114 provided non-inferior immune responses to 13 shared serotypes and superior immune responses to additional serotypes 22F and 33F.     

Immunogenicity and safety of a liquid Pentavalent (DTwP-Hb-Hib) combination vaccine manufactured by Human Biologicals Institute in 6–8 weeks old healthy infants: A phase III,randomized, single blind,non-inferiority study

BackgroundA liquid Pentavalent (DTwP-Hb-Hib) combination vaccine, developed by Human Biologicals Institute, underwent a Phase III clinical study in India. In this randomized, single blind, non-inferiority study, the immunogenicity and safety of this Investigational vaccine was compared with Pentavac SD® vaccine in 6–8 weeks old healthy infants.MethodsA total of 405 healthy infants aged 6–8 weeks old were randomized in 2:1 ratio to receive three doses of either the Investigational liquid Pentavalent (DTwP-Hb-Hib) combination vaccine or Pentavac SD® vaccine at four to six weeks interval. Immunogenicity was compared by estimation of antibody titers before the first dose and 4–6 weeks after the third dose of vaccination. Safety of each vaccine was assessed and compared by collection of data on solicited and unsolicited adverse events throughout the study period.ResultsOut of a total of 405 enrolled subjects, 387 subjects completed the study. The seroconversion rates, seroprotection rates and geometric mean titres of the Investigational liquid Pentavalent (DTwP-Hb-Hib) combination vaccine group were found to be comparable and non-inferior to the Pentavac SD® vaccine group at 4–6 weeks after the third dose of vaccination. Pain, erythema and swelling at the site of injection were found to be the most common local adverse events whereas fever, irritability and unusual crying were found to be the most common systemic adverse events in both the vaccine groups. No vaccine related serious adverse event was reported. In this study, both the Investigational vaccine as well as the Comparator vaccine were found to be immunogenic and well tolerated.ConclusionAfter assessment of the results of the study it was concluded that the Investigational liquid Pentavalent (DTwP-Hb-Hib) combination vaccine developed by Human Biologicals Institute was immunogenic and safe when administered to infants aged 6–8 weeks and was non-inferior in immunogenicity and safety to Pentavac SD® vaccine.Clinical Trial Registry of India Identifier: CTRI/2016/01/006541.     

A randomized phase 3 trial of the immunogenicity and safety of coadministration of a live-attenuated tetravalent dengue vaccine (TAK-003) and an inactivated hepatitis a (HAV) virus vaccine in a dengue non-endemic country

BackgroundVaccination against hepatitis A virus (HAV) is largely recommended for travelers worldwide. Concurrent dengue and HAV vaccination may be desired in parallel for travelers to countries where both diseases are endemic. This randomized, observer-blind, phase 3 trial evaluated coadministration of HAV vaccine with tetravalent dengue vaccine (TAK-003) in healthy adults aged 18–60 years living in the UK.MethodsParticipants were randomized (1:1:1) to receive HAV vaccine and placebo on Day 1, and placebo on Day 90 (Group 1), TAK-003 and placebo on Day 1, and TAK-003 on Day 90 (Group 2), or TAK-003 and HAV vaccine on Day 1, and TAK-003 on Day 90 (Group 3). The primary objective was non-inferiority of HAV seroprotection rate (anti-HAV ≥ 12.5 mIU/mL) in Group 3 versus Group 1, one month post-first vaccination (Day 30) in HAV-naïve and dengue-naïve participants. Sensitivity analyses were performed on combinations of baseline HAV and dengue serostatus. Secondary objectives included dengue seropositivity one month post-second vaccination (Day 120), HAV geometric mean concentrations (GMCs), and safety.Results900 participants were randomized. On Day 30, HAV seroprotection rates were non-inferior following coadministration of HAV and TAK-003 (Group 3: 98.7 %) to HAV administration alone (Group 1: 97.1 %; difference: ?1.68, 95 % CI: ?8.91 to 4.28). Sensitivity analyses including participants who were neither HAV-naïve nor DENV-naïve at baseline supported this finding. Anti-HAV GMCs on Day 30 were 82.1 (95 % CI: 62.9–107.1) mIU/mL in Group 1 and 93.0 (76.1–113.6) mIU/mL in Group 3. By Day 120, 90.9–96.8 % of TAK-003 recipients were seropositive (neutralizing antibody titer > 10) to all four dengue serotypes. Coadministration of HAV vaccine and TAK-003 was well tolerated, with no important safety risks identified.ConclusionImmune responses following coadministration of HAV vaccine and TAK-003 were non-inferior to administration of HAV vaccine alone. The results support the coadministration of HAV vaccine and TAK-003 with no adverse impact on immunogenicity, safety, and reactogenicity of either vaccine.ClinicalTrials.gov registration: NCT03525119.     

Ten-year follow-up on efficacy,immunogenicity and safety of two doses of a combined measles-mumps-rubella-varicella vaccine or one dose of monovalent varicella vaccine: Results from five East European countries

BackgroundWe assessed the 10-year efficacy, immunogenicity and safety of two doses of a combined measles-mumps-rubella-varicella vaccine (MMRV) or one dose of a monovalent varicella vaccine (V) in children from Czech Republic, Lithuania, Poland, Romania and Slovakia.MethodsThis was a phase IIIB follow-up of an observer-blind, randomized, controlled trial (NCT00226499). In phase A, healthy children aged 12–22 months from 10 European countries were randomized in a 3:3:1 ratio to receive two doses of MMRV (MMRV group), one dose of MMR followed by one dose of V (MMR + V group), or two doses of MMR (MMR; control group), 42 days apart. Vaccine efficacy (VE) against varicella (confirmed by viral DNA detection or epidemiological link and clinical assessment) was calculated with 95% confidence intervals using Cox proportional hazards regression model. Immunogenicity was assessed as seropositivity rates and geometric mean concentrations (GMCs). Solicited and unsolicited adverse events (AEs) and serious AEs (SAEs) were recorded.ResultsA total of 3705 children were vaccinated (1590, MMRV group; 1586, MMR + V group; 529, MMR group). There were 663 confirmed varicella cases (47, MMRV group; 349, MMR + V group; 267, MMR group). VE ranged between 95.4% (Lithuania) and 97.4% (Slovakia) in the MMRV group and between 59.3% (Lithuania) and 74% (Slovakia) in the MMR + V group. At year 10, seropositivity rates were 99.5%–100% in the MMRV group, 98%–100% in the MMR + V group and 50%–100% in the MMR control group, and the anti-VZV antibody GMCs were comparable between MMRV and MMR + V groups. The occurrence of solicited and unsolicited AEs was similar across groups and no SAE was considered as vaccination-related. No new safety concerns were identified.ConclusionsOur results indicated that two doses of varicella zoster virus-containing vaccine provided better protection than one dose against varicella and induced antibody responses that persisted 10 years post-vaccination.