BCG vaccine safety in COVID-19 convalescent adults: BATTLE a randomized controlled trial

IntroductionThe safety of BCG revaccination is uncertain and there is no data on its use in patients with COVID-19.MethodsCOVID-19 convalescent adults confirmed by SARS-CoV-2 RT-PCR in South-America were 1:1 randomized in the first 14 days of symptoms to BCG intradermal vaccine or placebo and evaluated for adverse events on days 7, 14, 21, and beyond 40 days. Clinical Trial Registration: NCT04369794.Results151 placebo and 148 BCG patients were included in the final analysis, with an average age of 40.7 years. No severe adverse event to BCG was reported. On day 7, 130 (87.8%) of the BCG recipients had local reaction, average size of 10.6 ± 6.4 mm, compared to only 2 (1.3%) placebos. Lesions gradually shrunk in size (mean 10.5 mm, 9.7 mm, and 6.8 mm at 14, 21, and beyond 40 days, respectively. The number of symptoms in any of the visits was not different between groups, and anosmia resolved earlier (25.7% vs. 37.1% at 7 days, OR = 1.70, 1.01–2.89, p = 0.035) in the BCG recipients.ConclusionThe BCG revaccination is safe in convalescent COVID-19 adults of a tuberculosis endemic region, regardless of tuberculin or IGRA test results. Local adverse events were similar though occurred earlier to that previously reported in children.     

Immunogenicity and safety of a second administration of 13-valent pneumococcal conjugate vaccine 5 years after initial vaccination in adults 50 years and older

BackgroundVaccination effectively reduces invasive disease and pneumonia caused by Streptococcus pneumoniae. However, waning antibody titers and the ability of revaccination to boost titers in older adults have been concerns. A study to describe antibody persistence after vaccination with 13-valent pneumococcal conjugate vaccine (PCV13) and response to revaccination 5 years after the initial dose was conducted.MethodsPneumococcal vaccine–naive subjects aged 50–59 years were randomized and vaccinated with PCV13 plus trivalent inactivated influenza vaccine concomitantly or 1 month apart, then revaccinated with PCV13 five years later. Antipneumococcal polysaccharide opsonophagocytic activity (OPA) geometric mean titers (GMTs) and immunoglobulin G (IgG) geometric mean concentrations (GMCs) were determined before and approximately 1 month after each vaccination. Targeted local reactions and systemic events were collected for 14 days, adverse events (AEs) for 1 month, and serious AEs (SAEs) for 6 months after each vaccination.ResultsOf 1116 randomized subjects, 727 were revaccinated at year 5. Between the time of initial vaccination and revaccination, OPA GMTs and IgG GMCs declined but remained higher than levels before initial vaccination for 12 of the 13 vaccine serotypes. One month after revaccination, OPA GMTs and IgG GMCs were comparable with, or higher than, levels observed 1 month after initial vaccination for most vaccine serotypes. Local reactions were mostly mild. AEs were reported by <5% and SAEs by <1% of subjects at 1 and 6 months after revaccination, respectively. No SAEs were vaccine-related.ConclusionsRevaccination of adults ≥50 years with PCV13 five years after primary vaccination was safe and immunogenic. Additionally, antibody titers were maintained for at least 5 years after vaccination. The vaccine stimulated a memory response as shown by enhanced responses that were maintained or enhanced by revaccination.ClinicalTrials.gov registrationNCT00521586.     

Bacillus Calmette–Guérin (BCG) vaccine safety surveillance in the Korea Adverse Event Reporting System using the tree-based scan statistic and conventional disproportionality-based algorithms

BackgroundSubstantial variations in the safety profiles of different formulations of the bacillus Calmette–Guérin (BCG) vaccine exist. Therefore, we aimed to detect safety signals of BCG vaccine for intradermal injection (BCG-ID) and percutaneous injection (BCG-PC) in the Korea Adverse Event Reporting System (KAERS).MethodsWe conducted a vaccine safety surveillance study from the adverse events (AEs) reported following BCG vaccine in the Korea Institute of Drug Safety and Risk Management KAERS Database (KIDS-KD) between 2005 and 2017. We used the tree-based scan statistic (TSS) and four disproportionality-based algorithms for signal detection: empirical Bayesian geometric mean; proportional reporting ratio; reporting odds ratio; and information component. The detected signals from each algorithm was compared with the known AEs of BCG vaccine (reference standard) to present positive predictive value (PPV) and area under the receiver operating curve (AUC).ResultsFrom the total of 52,191 vaccine-related AE pairs, 963 AE pairs were reported following the BCG vaccine, in which BCG-ID and –PC accounted for 71.1% and 28.9%, respectively. Overall, 97.2% of AE reports were non-serious; lymphadenopathy (583/963; 50.3%) and injection site discharge (193/963; 20.0%) were the most commonly reported AEs detected by all algorithms. Tuberculous osteitis was reported solely from BCG-PC (15/279; 5.4%), while most of the AEs from BCG-ID were related to injection site complications. The TSS demonstrated the best balance of the performance measures, with PPV and AUC of 66.7% and 63.1%, respectively.ConclusionsTSS was successfully applied in the KAERS to detect safety signals of BCG vaccine. In addition, difference in the safety profiles of BCG-ID and BCG-PC warrants further investigation to confirm our findings. Although TSS performed the best in our study, caution should be taken when interpreting the results owing to the lack of a robust “gold standard” and the relatively small number of reports for data mining.     

Adverse reactions to the Bacillus Calmette–Guérin (BCG) vaccine in new-born infants—an evaluation of the Danish strain 1331 SSI in a randomized clinical trial

ObjectiveTo evaluate adverse reactions of the Bacillus Calmette–Guérin (BCG) Statens Serum Institut (SSI) (Danish strain 1331) used as intervention in a randomized clinical trial.DesignA randomized clinical multicenter trial, The Danish Calmette Study, randomizing newborns to BCG or no intervention. Follow-up until 13 months of age.SettingPediatric and maternity wards at three Danish university hospitals.ParticipantsAll women planning to give birth at the three study sites (n = 16,521) during the recruitment period were invited to participate in the study. Four thousand one hundred and eighty four families consented to participate and 4262 children, gestational age 32 weeks and above, were randomized: 2129 to BCG vaccine and 2133 to no vaccine. None of the participants withdrew because of adverse reactions.Main outcome and measureTrial-registered adverse reactions after BCG vaccination at birth. Follow-up at 3 and 13 months by telephone interviews and clinical examinations.ResultsAmong the 2118 BCG-vaccinated children we registered no cases of severe unexpected adverse reaction related to BCG vaccination and no cases of disseminated BCG disease. Two cases of regional lymphadenitis were hospitalized and thus classified as serious adverse reactions related to BCG. The most severe adverse reactions were 10 cases of suppurative lymphadenitis. This was nearly a fivefold increase compared to what was expected based on the summary of product characteristics of the vaccine. All cases were treated conservatively and recovered. Six of 10 (60%) families of children experiencing suppurative lymphadenitis compared to 117/2071 (6%) of those with no lymphadenitis indicated that the vaccine had more adverse effects than expected (p-value <0.001).Conclusions and relevanceBCG vaccination was associated with only mild morbidity and no mortality. A higher incidence of suppurative lymphadenitis than expected was observed. All children were treated conservatively without sequelae or complications.Trial registrationTrial registration number NCT01694108 at www.clinicaltrials.gov     

Safety and reactogenicity of BCG revaccination with isoniazid pretreatment in TST positive adults

Rationale

Global tuberculosis (TB) control may require mass vaccination with a new TB vaccine, such as a recombinant bacille Calmette Guerin (BCG) or attenuated Mycobacterium tuberculosis (MTB). The safety profile of live mycobacterial vaccines in latently infected adults with prior infant BCG vaccination is unknown.

Objectives

Evaluate safety and reactogenicity of BCG revaccination, with or without isoniazid (INH) pretreatment, in adults with latent MTB infection (LTBI).

Methods

Eighty-two healthy, HIV uninfected, South African adults, with a BCG scar and tuberculin skin test (TST) diameter ≥15 mm, were randomized to receive 6 months of INH, starting either before, or 6 months after, intradermal revaccination with BCG Vaccine SSI (Statens Serum Institut, Copenhagen). Safety and reactogenicity data are reported through 3 months post BCG revaccination.

Results

Baseline characteristics were similar between treatment arms. Mean baseline TST diameter was 20 ± 4 mm. Seventy-two subjects received BCG revaccination. Injection site erythema (68%) and induration (86%) peaked 1 week after revaccination. Ulceration (76%) peaked at 2 weeks, and resolved by 3 months in all but 3 subjects. Diameter of ulceration was >10 mm in only 8%, but a residual scar was common (85%). No regional lymphadenitis or serious morbidity related to BCG was seen. Reactogenicity was not affected by INH pretreatment.

Conclusion

BCG revaccination of MTB infected adults is safe, well tolerated, and reactogenicity is similar to that of primary BCG vaccination. Clinical trials of live recombinant BCG or attenuated MTB vaccines may be considered in latently infected adults, with or without INH pretreatment (ClinicalTrials.gov identifier: NCT01119521).     

Safety of vaccines used for routine immunization in the United States: An updated systematic review and meta-analysis

BackgroundUnderstanding the safety of vaccines is critical to inform decisions about vaccination. Our objective was to conduct a systematic review of the safety of vaccines recommended for children, adults, and pregnant women in the United States.MethodsWe searched the literature in November 2020 to update a 2014 Agency for Healthcare Research and Quality review by integrating newly available data. Studies of vaccines that used a comparator and reported the presence or absence of key adverse events were eligible. Adhering to Evidence-based Practice Center methodology, we assessed the strength of evidence (SoE) for all evidence statements. The systematic review is registered in PROSPERO (CRD42020180089).ResultsOf 56,603 reviewed citations, 338 studies reported in 518 publications met inclusion criteria. For children, SoE was high for no increased risk of autism following measles, mumps, and rubella (MMR) vaccine. SoE was high for increased risk of febrile seizures with MMR. There was no evidence of increased risk of  intussusception with rotavirus vaccine at the latest follow-up (moderate SoE), nor of diabetes (high SoE). There was no evidence of increased risk or insufficient evidence for key adverse events for newer vaccines such as 9-valent human papillomavirus and meningococcal B vaccines. For adults, there was no evidence of increased risk (varied SoE) or insufficient evidence for key adverse events for the new adjuvanted inactivated influenza vaccine and recombinant adjuvanted zoster vaccine. We found no evidence of increased risk (varied SoE) for key adverse events among pregnant women following tetanus, diphtheria, and acellular pertussis vaccine, including stillbirth (moderate SoE).ConclusionsAcross a large body of research we found few associations of vaccines and serious key adverse events; however, rare events are challenging to study. Any adverse events should be weighed against the protective benefits that vaccines provide.     

Adverse events following vaccination with an inactivated,Vero cell culture-derived Japanese encephalitis vaccine in the United States, 2009–2012

BackgroundIn March 2009, the U.S. Food and Drug Administration licensed an inactivated, Vero cell culture-derived Japanese encephalitis vaccine (JE-VC [Ixiaro]) for use in adults. The vaccine was licensed based on clinical trial safety data in 3558 JE-VC recipients. It is essential to monitor post-licensure surveillance data to evaluate the safety of JE-VC because rare adverse events may not be detected until the vaccine is administered to a larger population.MethodsWe reviewed adverse events reported to the U.S. Vaccine Adverse Event Reporting System (VAERS) for adults (≥17 years) who received JE-VC from May 2009 through April 2012. Adverse event reporting rates were calculated using 275,848 JE-VC doses distributed.ResultsOver the 3 year period, 42 adverse events following vaccination with JE-VC were reported to VAERS for an overall reporting rate of 15.2 adverse events per 100,000 doses distributed. Of the 42 total reports, 5 (12%) were classified as serious for a reporting rate of 1.8 per 100,000 doses distributed; there were no deaths. Hypersensitivity reactions (N = 12) were the most commonly reported type of adverse event, with a rate of 4.4 per 100,000 doses distributed; no cases of anaphylaxis were reported. Three adverse events of the central nervous system were reported (one case of encephalitis and two seizures) for a rate of 1.1 per 100,000; all occurred after receipt of JE-VC with other vaccines.ConclusionsThese post-marketing surveillance data suggest a good safety profile for JE-VC consistent with findings from pre-licensure clinical trials. Post-licensure safety data should continue to be monitored for any evidence of rare serious or neurologic adverse events.     

Safety of live vaccinations on immunosuppressive therapy in patients with immune-mediated inflammatory diseases,solid organ transplantation or after bone-marrow transplantation – A systematic review of randomized trials,observational studies and case reports

BackgroundLive vaccines are generally contraindicated on immunosuppressive therapy due to safety concerns. However, data are limited to corroborate this practice.ObjectivesTo estimate the safety of live vaccinations in patients with immune-mediated inflammatory diseases (IMID) or solid organ transplantation (SOT) on immunosuppressive treatment and in patients after bone-marrow transplantation (BMT).Data SourcesA search was conducted in electronic databases (Cochrane, Pubmed, Embase) and additional literature was identified by targeted searches.Eligibility criteriaRandomized trials, observational studies and case reports.PopulationPatients with IMID or SOT on immunosuppressive treatment and BMT patients <2 years after transplantation.Intervention/vaccinations looked atLive vaccinations: mumps, measles, rubella (MMR), yellow fever (YF), varicella vaccine (VV), herpes zoster (HZ), oral typhoid, oral polio, rotavirus, Bacillus Calmette–Guérin (BCG), smallpox.Data extractionOne author performed the data extraction using predefined data fields. It was cross-checked by two other authors.Results7305 articles were identified and 64 articles were included: 40 on IMID, 16 on SOT and 8 on BMT patients. In most studies, the administration of live vaccines was safe. However, some serious vaccine-related adverse events occurred. 32 participants developed an infection with the vaccine strain; in most cases the infection was mild. However, in two patients fatal infections were reported: a patient with RA/SLE overlap who started MTX/dexamethasone treatment four days after the YFV developed a yellow fever vaccine-associated viscerotropic disease (YEL-AVD) and died. The particular vaccine lot was found to be associated with a more than 20 times risk of YEL-AVD. One infant whose mother was under infliximab treatment during pregnancy received the BCG vaccine at the age of three months and developed disseminated BCG infection and died. An immunogenicity assessment was performed in 43 studies. In most cases the patients developed satisfactory seroprotection rates. In the IMID group, YFV and VV demonstrated high seroconversion rates. MTX and tumor necrosis factor inhibitory therapy appeared to reduce immune responses to VV and HZ vaccine, but not to MMR and YF-revaccination. Seroconversion in SOT and BMT patients showed mostly higher rates for rubella than for measles, mumps and varicella.LimitationsRisk of bias was high in the majority of studies since 39 of them were observational and 17 were case series/case reports. Only eight studies were randomized trials. BMT patient numbers included in this review were low.ConclusionsAlthough live vaccinations were safe and sufficiently immunogenic in most studies, some serious reactions and vaccine-related infections were reported in immunosuppressed IMID and SOT patients. Apart from mild vaccine-related infections MMR and VV vaccines were safe when administered less than two years after BMT.Implications of key findingsUntil further data are available, live vaccinations under most immunosuppressive treatments should only be administered after a careful risk benefit assessment of medications and dosages.FundingNone.     

Modelling the effect of discontinuing universal Bacillus Calmette-Guérin vaccination in an intermediate tuberculosis burden setting

BackgroundBacillus Calmette-Guérin (BCG) vaccination is a widely-used public health intervention for tuberculosis (TB) control. In Taiwan, like other intermediate TB burden settings, steadily declining TB incidence raises important questions on whether universal BCG vaccination should be discontinued. Recent surveys on adverse events following immunisation, such as BCG-induced osteomyelitis/osteitis, also suggest a need to re-evaluate the vaccination programme.MethodsWe developed an age-structured transmission dynamic model, calibrated to population demography and age-specific TB notification rates in Taiwan. We adopted ‘weak-protection’ and ‘strong-protection’ scenarios, representing a range of characteristics including the duration of BCG protection and vaccine efficacies against TB infection and progression. We estimated averted disability-adjusted life years (DALYs) and incremental costs over 10 years after discontinuing universal BCG vaccination in 2018, 2035, and 2050. We also examined the potential impact of ‘surveillance-guided’ discontinuation, triggered once notification rates fall to a given threshold.ResultsIn the weak-protection scenario, discontinuing BCG would result in 2.8 (95% uncertainty range: 2.3, 3.1) additional notified TB cases and −4.1 (−7.7, 0.8) net averted DALYs over 2018–2027. In the strong-protection scenario, 82.9 (72.6, 91.6) additional cases and −402.7 (−506.6, −301.2) averted DALYs would be reported, suggesting a robustly negative health impact. However, in this vaccine scenario, there could be an overall health benefit if BCG is discontinued once TB notification falls below 5 per 100,000 population. The most influential vaccine characteristic for the net health impact is the vaccine efficacy against progression to pulmonary TB. In financial terms, the eliminated cost of the vaccination programme substantially outweighed the incremental cost for TB treatment regardless of BCG protection.ConclusionsBCG discontinuation may be warranted in intermediate burden settings, depending on the quality of vaccine protection, and the potential for refocusing on other TB control activities for earlier detection and treatment.     

Safety and immunogenicity of revaccination with reduced dose intradermal and standard dose intramuscular influenza vaccines in adults 18–64 years of age

Background

This clinical trial examined the safety and immunogenicity of annual revaccination with Fluzone^® Intradermal (Sanofi Pasteur, Swiftwater, PA) vaccine compared to a standard intramuscular (IM) split-virion trivalent influenza vaccine (Fluzone^®, Sanofi Pasteur).

Methods

This phase II, active-controlled, multi-centre, open-label trial was conducted in 2009 and 2010, and enrolled 1250 adults 18–64 years of age who were randomly selected from participants in a phase III influenza vaccine trial the previous year (NCT00772109). Subjects who had previously received the ID vaccine were randomized 2:1 to be revaccinated with the ID or IM vaccine and those who previously received the IM vaccine were randomized 1:1. Solicited reactions were recorded on the day of vaccination and continuing for the next 7 days, non-serious adverse events for 28 days, and serious adverse events for 6 months after vaccination. Hemagglutination inhibition antibody titres were assessed pre-vaccination and at day 28.

Results

Reactions were well-tolerated and resolved in the first 7 days, but erythema, induration, swelling, pruritus and ecchymosis were reported by more subjects receiving the ID vaccine than the IM vaccine. Compared to receipt of IM vaccine in the previous year, ID vaccine in the previous year led to statistically higher rates of erythema, swelling and induration after IM vaccine in the second year. Injection-site pain and systemic reactions did not differ between ID and IM vaccines. No treatment-related serious adverse events were reported. Geometric mean antibody titres, seroprotection rates, and seroconversion rates were non-inferior for the ID and IM vaccines for all three viral strains.

Conclusions

The ID vaccine was as immunogenic as the IM vaccine, and raised no safety concerns. It can be used interchangeably with the IM vaccine for annual revaccination in adults 18–64 years of age in consecutive years without safety concerns.     

Adverse events following vaccination with an inactivated,Vero cell culture-derived Japanese encephalitis vaccine in the United States, 2012–2016

BackgroundIn March 2009, the U.S. Food and Drug Administration licensed an inactivated Vero cell culture-derived Japanese encephalitis vaccine (JE-VC [IXIARO®]) for use in persons aged ≥17 years. In 2013, licensure was extended to include children aged ≥2 months. A previous analysis reviewed adverse events reported to the U.S. Vaccine Adverse Event Reporting System (VAERS) from May 2009 through April 2012.MethodsWe reviewed adverse events reported to VAERS following JE-VC administered from May 1, 2012 through April 30, 2016. Adverse event reporting rates were calculated using 802,229 doses distributed.ResultsDuring the 4-year period, 119 adverse event reports were received for a reporting rate of 14.8 per 100,000 doses distributed. Nine (8%) adverse events were classified as serious for a reporting rate of 1.1 per 100,000 distributed. The most commonly reported event was hypersensitivity (n = 24; 20%) for a rate of 3.0 per 100,000 doses distributed; 1 anaphylaxis event was reported. Ten (8%) neurologic events were reported for a rate of 1.2 per 100,000 doses distributed; 2 events were classified as seizures. Sixty-three (53%) adverse events occurred after a first dose of JE-VC. Eighty (67%) adverse events occurred after administration of JE-VC with other vaccines. Eleven (9%) adverse events were reported in children; 1 was considered serious.ConclusionsThese data continue to support the generally favorable safety profile of JE-VC. Reporting rates of adverse events were similar to those of the previous analysis. Although reporting rates of adverse events in children could not be calculated, there were low numbers of reported events in this age group. Post-licensure adverse event surveillance for this relatively new vaccine continues to be important to monitor adverse event reporting rates and identify possible rare serious events.     

Evidence of an effect of BCG revaccination on incidence of tuberculosis in school-aged children in Brazil: second report of the BCG-REVAC cluster-randomised trial

BCG revaccination is still used in some tuberculosis endemic countries. Until now, the little evidence available suggested that BCG revaccination confers very limited additional protection, although there was no information on whether protection depends on the setting and age of revaccination, or if protection increases with time since vaccination. Here we report on an extended follow up of the BCG-REVAC trial, a cluster randomised trial conducted in the Brazilian cities Salvador and Manaus including over 200,000 children aged 7-14 years aimed to evaluate the efficacy of BCG revaccination in children who had received neonatal BCG vaccination. With the extended follow-up (9 years) and the additional cases accrued we now have enough power to report vaccine efficacy separately for the two cities (with different distances from Equator and presumably different prevalence of non-tuberculosis mycobacteria), and by age at vaccination and clinical form. The overall vaccine efficacy was 12% (−2 to 24%) as compared to 9% (−16 to 29%) for the 5-year follow up. Vaccine efficacy was higher in Salvador (19%, 3 to 33%) than in Manaus (1%, −27 to 27%) with the highest vaccine efficacy in children from Salvador aged <11 years at revaccination (33%, 3 to 54%). The findings are in line with the hypothesis that BCG vaccination offers higher efficacy in low NTMb prevalence, and show that revaccination with BCG can offer weak protection in selected subgroups.     

Repeated exposure to an MF-59 adjuvanted quadrivalent subunit influenza vaccine (aQIV) in children: Results of two revaccination studies

BackgroundPediatric adjuvanted seasonal influenza vaccines induce higher immune responses and have the potential to confer better protection against influenza among young vaccine-naïve children. Limited data describe benefits and risks of repeated administration of adjuvanted influenza vaccines in children. Two revaccination studies assess the safety and immunogenicity of repeated exposure to an MF59-adjuvanted quadrivalent influenza vaccine (aQIV; Fluad®) compared to routine non-adjuvanted quadrivalent influenza vaccine (QIV).MethodsChildren previously enrolled in the parent study, who received vaccination with aQIV or nonadjuvanted influenza vaccine (TIV or QIV), were recruited in Season 1 (n = 607) or Season 2 (n = 1601) of the extension trials. Season 1 participants remained in their original randomization groups (aQIV-aQIV or TIV-QIV); Season 2 subjects were re-randomized to either vaccine, resulting in four groups (aQIV-aQIV, aQIV-QIV, QIV-aQIV, or QIV-QIV). All subjects received a single-dose vaccination. Blood samples were taken for immunogenicity assessment prior to vaccination and 21 and 180 days after vaccination. Reactogenicity (Days 1–7) and safety were assessed in all subjects.ResultsHemagglutination inhibition (HI) geometric mean titer (GMT) ratios demonstrated superiority of aQIV revaccination over QIV revaccination for all strains in Season 1 and for A/H1N1, B/Yamagata, and B/Victoria in Season 2. Higher HI titers against heterologous influenza strains were observed after aQIV vaccination during both seasons. Mild to moderate severity and short duration reactogenicity was more common in the aQIV than QIV groups, but the overall safety profiles were similar to the parent study.ConclusionThe safety and immunogenicity results from this study demonstrate benefit of aQIV for both priming and revaccination of children aged 12 months to 7 years.     

A first-in-human phase 1 trial to evaluate the safety and immunogenicity of the candidate tuberculosis vaccine MVA85A-IMX313, administered to BCG-vaccinated adults

IntroductionThere is an urgent need for a new and effective tuberculosis vaccine because BCG does not sufficiently prevent pulmonary disease. IMX313 is a novel carrier protein designed to improve cellular and humoral immunity. MVA85A-IMX313 is a novel vaccine candidate designed to boost immunity primed by bacillus Calmette-Guérin (BCG) that has been immunogenic in pre-clinical studies. This is the first evaluation of IMX313 delivered as MVA85A-IMX313 in humans.MethodsIn this phase 1, open-label first-in-human trial, 30 healthy previously BCG-vaccinated adults were enrolled into three treatment groups and vaccinated with low dose MVA85A-IMX313 (group A), standard dose MVA85A-IMX313 (group B), or MVA85A (group C). Volunteers were followed up for 6 months for safety and immunogenicity assessment.ResultsThe majority of adverse events were mild and there were no vaccine-related serious AEs. Both MVA85A-IMX313 and MVA85A induced a significant increase in IFN-γ ELISpot responses. There were no significant differences between the Ag85A ELISpot and intracellular cytokine responses between the two study groups B (MVA85A-IMX313) and C (MVA85A) at any time point post-vaccination.ConclusionMVA85A-IMX313 was well tolerated and immunogenic. There was no significant difference in the number of vaccine-related, local or systemic adverse reactions between MVA85A and MVA85A-IMX313 groups. The mycobacteria-specific cellular immune responses induced by MVA85A-IMX313 were not significantly different to those detected in the MVA85A group. In light of this encouraging safety data, further work to improve the potency of molecular adjuvants like IMX313 is merited.This trial was registered on clinicatrials.gov ref. NCT01879163.     

Safety monitoring of COVID-19 vaccination among adolescents aged 12 to 17 years old in the Republic of Korea

ObjectivesThis study aimed to disseminate information on coronavirus disease 2019 (COVID-19) vaccine safety among adolescents aged 12 to 17 years in the Republic of Korea.Methods Two databases were used to assess COVID-19 vaccine safety in adolescents aged 12 to 17 years who completed the primary Pfizer-BioNTech vaccination series. Adverse events reported to the web-based COVID-19 vaccination management system (CVMS) and collected in the text message-based system were analyzed.Results From March 5, 2021 to February 13, 2022, 12,216 adverse events among 12- to 17-year-olds were reported to the CVMS, of which 97.1% were non-serious adverse events and 2.9% were serious adverse events, including 85 suspected cases of anaphylaxis, 74 suspected cases of myocarditis and/or pericarditis, and 2 deaths. From December 13, 2021 to January 26, 2022, 10,389 adolescents responded to a text message survey, and local/systemic adverse events were more common after dose 2 than after dose 1. The most commonly reported events following either vaccine dose were pain at the injection site, headache, fatigue/tiredness, and myalgia.ConclusionThe overall results are consistent with previous findings; the great majority of adverse events were non-serious, and serious adverse events were rare among adolescents aged 12 to 17 years following Pfizer-BioNTech COVID-19 vaccination.     

COVID-19 vaccine safety monitoring in Republic of Korea from February 26, 2021 to October 31, 2021

ObjectivesThis study aimed to present data on reported adverse events following coronavirus disease 2019 (COVID-19) vaccination in Republic of Korea from February 26 to October 31, 2021, and to determine whether any significant patterns emerged from an analysis of the characteristics of suspected adverse event cases for each type of vaccine.MethodsAdverse events following COVID-19 vaccination reported by medical doctors and forensic pathologists were analyzed. Cases of suspected anaphylaxis were classified using the Brighton Collaboration definition.ResultsBy October 31, 2021, a total of 353,535 (0.45%) adverse events were reported after 78,416,802 COVID-19 vaccine doses. Of the adverse events, 96.4% were non-serious and 3.6% were serious. The most frequently reported adverse events were headache, myalgia, and dizziness. Of the 835 reported deaths after COVID-19 vaccination, 2 vaccine-related deaths were confirmed. Suspected anaphylaxis was confirmed in 454 cases using the Brighton Collaboration definition.ConclusionThe commonly reported symptoms were similar to those described in clinical trials. Most reported adverse events were non-serious, and the reporting rate of adverse events following COVID-19 vaccination was higher in women than in men (581 vs. 315 per 100,000 vaccinations). Confirmed anaphylaxis was reported in 5.8 cases per 1,000,000 vaccinations.     

Vaccinomics: A scoping review

BackgroundThis scoping review summarizes a key aspect of vaccinomics by collating known associations between heterogeneity in human genetics and vaccine immunogenicity and safety.MethodsWe searched PubMed for articles in English using terms covering vaccines routinely recommended to the general US population, their effects, and genetics/genomics. Included studies were controlled and demonstrated statistically significant associations with vaccine immunogenicity or safety. Studies of Pandemrix®, an influenza vaccine previously used in Europe, were also included, due to its widely publicized genetically mediated association with narcolepsy.FindingsOf the 2,300 articles manually screened, 214 were included for data extraction. Six included articles examined genetic influences on vaccine safety; the rest examined vaccine immunogenicity. Hepatitis B vaccine immunogenicity was reported in 92 articles and associated with 277 genetic determinants across 117 genes. Thirty-three articles identified 291 genetic determinants across 118 genes associated with measles vaccine immunogenicity, 22 articles identified 311 genetic determinants across 110 genes associated with rubella vaccine immunogenicity, and 25 articles identified 48 genetic determinants across 34 genes associated with influenza vaccine immunogenicity. Other vaccines had fewer than 10 studies each identifying genetic determinants of their immunogenicity. Genetic associations were reported with 4 adverse events following influenza vaccination (narcolepsy, GBS, GCA/PMR, high temperature) and 2 adverse events following measles vaccination (fever, febrile seizure).ConclusionThis scoping review identified numerous genetic associations with vaccine immunogenicity and several genetic associations with vaccine safety. Most associations were only reported in one study. This illustrates both the potential of and need for investment in vaccinomics. Current research in this field is focused on systems and genetic-based studies designed to identify risk signatures for serious vaccine reactions or diminished vaccine immunogenicity. Such research could bolster our ability to develop safer and more effective vaccines.     

Is there a difference in the immune response,efficacy, effectiveness and safety of seasonal influenza vaccine in males and females? – A systematic review

IntroductionSeasonal influenza is an important cause of morbidity and mortality, despite being vaccine-preventable. Sex factors (genes and hormones) seem to impact individuals’ susceptibility to infectious diseases and their response to vaccination. However, most vaccine studies do not explicitly assess sex differences in vaccine response, but rather adjust for sex.MethodsWe conducted a systematic review to analyze immunogenicity, efficacy, effectiveness and/or safety of seasonal influenza vaccine data stratified by sex. We searched PubMed, EMBASE, CINAHL, Web of Science and clinicaltrials.gov for observational studies and phase III/IV trials from January 1990 to June 2018, published in English or French. Two reviewers independently screened all references, then proceeded to data extraction and quality assessment using the Cochrane tools (RoB and ROBINS-I) on included studies.ResultsOf the 5,745 citations retrieved, 46 studies were included in the SR. Overall, 18 studies assessed immunogenicity, 1 estimated efficacy, 6 measured effectiveness and 25 evaluated safety of seasonal influenza vaccine in females and males (four studies reported on two sex-stratified outcomes concomitantly).ConclusionNo clear conclusion could be drawn regarding the effect of sex on the immunogenicity and effectiveness of seasonal influenza vaccine, but higher rates of adverse events following immunization (AEFIs) were reported in females. The heterogeneity of data and studies’ low quality prevented us from conducting a meta-analysis. There is a need to emphasize on the appropriate use of the terms sex and gender in biomedical research. Evidence of higher quality is needed to better understand sex differences in response to influenza vaccine.     

Safety profile of the varicella vaccine (Oka vaccine strain) based on reported cases from 2005 to 2015 in Japan

BackgroundAs of 2014, routine vaccination strategies in Japan have included the varicella vaccine. Given the widespread use of the vaccine, it is important to investigate the safety profile of the vaccine strain, Oka/Biken varicella, in Japanese patients.MethodsReports of adverse events associated with varicella vaccination between 2005 and 2015 were retrospectively reviewed. Virological analysis was performed on clinical specimens collected from some of the reported cases to determine whether the etiological agent was the wild-type or Oka vaccine–strains.ResultsThere were 351 reports (3.71/100,000 doses) of adverse events during the observation period. Among the 351 reports, there were 88 reports (0.93/100,000 doses) of varicella-like and 66 reports (0.70/100,000 doses) of zoster-like skin rashes. The wild-type strain induced varicella-like skin rashes earlier than the Oka vaccine strain. The Oka vaccine strain induced zoster-like skin rashes in younger patients compared to the wild-type strain. The onset of zoster-like skin rashes after vaccination was earlier in patients vaccinated with the Oka vaccine–type strain.ConclusionThe Oka/Biken vaccine is generally safe and well tolerated in Japan. Clinical aspects of adverse reactions caused by the Oka vaccine strain were consistent with previous reports from the United States and Europe.     

Randomised revaccination with pneumococcal polysaccharide or conjugate vaccine in asplenic children previously vaccinated with polysaccharide vaccine

OBJECTIVE: Asplenic children are at high risk of invasive pneumococcal infection. In this group, the American Academy of Pediatrics recommends a single revaccination with the 23-valent polysaccharide vaccine (PSV23) 3-5 years after a previous PSV23 dose. Despite potential advantages, there are few data available regarding the safety and immunogenicity of the heptavalent pneumococcal conjugate vaccine (PCV7) in this population. The aim of the study was to prospectively determine and to compare, in asplenic children, the vaccine specific antibody titres against the seven serotypes included in the PCV7 after administration of one dose of PCV7 or of PSV23, 3 years or more after an initial vaccination with PSV23. PATIENTS AND METHODS: In this randomised, single-centre study, antibody titres were monitored at baseline, at 1 and 6 months after revaccination in 21 children with anatomic or functional asplenia. Response was considered as positive when there was a four-fold increase in antibody titres from baseline. RESULTS: The most frequently reported adverse events were local reactions in 7/11 of PCV7 subjects and in 5/8 of PSV23 subjects, and general reactions (loss of appetite, sleepiness) in 5/11 of PCV7 subjects and in 1/8 of PSV23 subjects; without any serious adverse events. One child in the PCV7 group had increased temperature (38.4 degrees C). At least half of the PCV7 children responded to four or five serotypes, while more than half of the PSV23 subjects responded to less than 3 serotypes (p=0.285). After 1 month, the immune response for serotype 23F was significantly greater after PCV7 vaccination than after PSV23 vaccination (p=0.036). CONCLUSIONS: PCV7 revaccination is safe and immunogenic in asplenic children previously vaccinated with PSV23, and could provide appropriate booster response in this high-risk population. The clinical repercussion on invasive pneumococcal diseases remains to be demonstrated.