A phase 1 dose-sparing,randomized clinical trial of seasonal trivalent inactivated influenza vaccine combined with MAS-1, a novel water-in-oil adjuvant/delivery system

BackgroundNew influenza vaccines are needed to increase vaccine efficacy. Adjuvants may allow hemagglutinin (HA) dose-sparing with enhanced immunogenicity. MAS-1 is an investigational low viscosity, free-flowing, water-in-oil emulsion-based adjuvant/delivery system comprised of stable nanoglobular aqueous droplets.MethodsA phase 1, double-blind, safety and immunogenicity, HA dose escalation, randomized clinical trial was conducted. MAS-1 adjuvant with 1, 3, 5 or 9 µg per HA derived from licensed seasonal trivalent high dose inactivated influenza vaccine (IIV, Fluzone HD 60 µg per HA) in a 0.3 mL dose were compared to standard dose IIV (Fluzone SD, 15 µg per HA). Safety was measured by reactogenicity, adverse events, and clinical laboratory tests. Serum hemagglutination inhibition (HAI) antibody titers were measured for immunogenicity.ResultsSeventy-two subjects, aged 18–47 years, received one dose of either 0.3 mL adjuvanted vaccine or SD IIV intramuscularly. Common injection site and systemic reactions post-vaccination were mild tenderness, induration, pain, headache, myalgia, malaise and fatigue. All reactions resolved within 14 days post-vaccination. Safety laboratory measures were not different between groups. Geometric mean antibody titers, geometric mean fold increases in antibody titer, seroconversion rates and seroprotection rates against vaccine strains were in general higher and of longer duration (day 85 and 169 visits) with MAS-1-adjuvanted IIV at all doses of HA compared with SD IIV. Adjuvanted vaccine induced higher antibody responses against a limited number of non-study vaccine influenza B and A/H3N2 viruses including ones from subsequent years.ConclusionMAS-1 adjuvant in a 0.3 mL dose volume provided HA dose-sparing effects without safety concerns and induced higher HAI antibody and seroconversion responses through at least 6 months, demonstrating potential to provide greater vaccine efficacy throughout an influenza season in younger adults. In summary, MAS-1 may provide enhanced, more durable and broader protective immunity compared with non-adjuvanted SD IIV.Clinical Trial Registry: ClinicalTrials.gov # NCT02500680.     

MAS-1, a novel water-in-oil adjuvant/delivery system,with reduced seasonal influenza vaccine hemagglutinin dose may enhance potency,durability and cross-reactivity of antibody responses in the elderly

BackgroundIncreased influenza vaccine efficacy is needed in the elderly at high-risk for morbidity and mortality due to influenza infection. Adjuvants may allow hemagglutinin (HA) dose-sparing with enhanced immunogenicity. MAS-1 is an investigational water-in-oil emulsion-based adjuvant/delivery system comprised of stable nanoglobular aqueous droplets.MethodsA phase 1, randomized, double-blind, safety and immunogenicity, adjuvant dose escalation trial was conducted in persons aged 65 years and older. MAS-1 adjuvant dose volumes at 0.3 mL or 0.5 mL containing 9 µg per HA derived from licensed seasonal trivalent influenza vaccine (IIV, Fluzone HD 60 µg per HA, Sanofi Pasteur) were compared to high dose (HD) IIV (Fluzone HD). Safety was measured by reactogenicity, adverse events, and safety laboratory measures. Immunogenicity was assessed by serum hemagglutination inhibition (HAI) antibody titers.ResultsForty-five subjects, aged 65–83 years, were randomly assigned to receive 9 µg per HA in 0.3 mL MAS-1 (15 subjects) or HD IIV (15 subjects) followed by groups randomly assigned to receive 9 µg per HA in 0.5 mL MAS-1 (10 subjects) or HD IIV (5 subjects). Injection site tenderness, induration, and pain, and headache, myalgia, malaise and fatigue were common, resolving before day 14 post-vaccination. Clinically significant late-onset injection site reactions occurred in four of ten subjects at the 0.5 mL adjuvant dose. Safety laboratory measures were within acceptable limits. MAS-1-adjuvanted IIV enhanced mean antibody titers, mean-fold increases in antibody titer, and seroconversion rates against vaccine strains for at least 168 days post-vaccination and enhanced cross-reactive antibodies against some non-study vaccine influenza viruses.ConclusionMAS-1 adjuvant provided HA dose-sparing without safety concerns at the 0.3 mL dose, but the 0.5 mL dose caused late injection site reactions. MAS-1-adjuvanted IIV induced higher HAI antibody responses with prolonged durability including against historical strains, thereby providing greater potential vaccine efficacy in the elderly throughout an influenza season.Clinical Trial Registry: ClinicalTrials.gov # NCT02500680.     

A preliminary report of a randomized controlled phase 2 trial of the safety and immunogenicity of mRNA-1273 SARS-CoV-2 vaccine

BackgroundVaccines are urgently needed to prevent the global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We assessed the safety and immunogenicity of vaccine candidate mRNA-1273, encoding the prefusion-stabilized spike protein of SARS-CoV-2.MethodsThis phase 2, randomized, observer-blind, placebo-controlled trial was conducted at 8 sites in the USA, in healthy adults aged ≥18 years with no known history or risk of SARS-CoV-2 infection, and had not previously received an investigational CoV vaccine or treatment. Participants were stratified into two age cohorts (≥18-<55 and ≥55) and were randomly assigned (1:1:1) to either 50 or 100 µg of mRNA-1273, or placebo administered as two intramuscular injections 28 days apart. The primary outcomes were safety, reactogenicity, and immunogenicity assessed by anti-SARS-CoV-2-spike binding antibody level (bAb). Secondary outcome was immunogenicity assessed by SARS-CoV-2 neutralizing antibody (nAb) response.ResultsBetween 29 May and 8 July 2020, 600 participants were randomized, 300 per age cohort. The most common solicited adverse reactions were pain at injection site, headache, and fatigue following each vaccination in both age cohorts. One serious adverse event deemed unrelated by the site investigator occurred 33 days post-vaccination one. mRNA-1273 induced bAb and nAb by 28 days post-vaccination one that were higher at the 100 µg dose relative to the 50 µg dose; this difference was less apparent post-vaccination two. Binding antibodies and nAb increased substantially by 14 days following the second vaccination (day 43) to levels exceeding those of convalescent sera and remained elevated through day 57.ConclusionsVaccination with mRNA-1273 resulted in significant immune responses to SARS-CoV-2 in participants 18 years and older, with an acceptable safety profile, confirming the safety and immunogenicity of 50 and 100 µg mRNA-1273 given as a 2 dose-regimen.ClinicalTrials.gov; NCT04405076.     

MenACWY-CRM conjugate vaccine booster dose given 4–6 years after priming: Results from a phase IIIb,multicenter, open label study in adolescents and adults

BackgroundVaccination strategies against bacterial meningitis vary across countries. In the United States, a single dose of quadrivalent meningococcal conjugate vaccine (MenACWY) is recommended at 11–12 years of age, with a booster dose approximately 5 years later. We assessed immune responses to a booster dose of MenACWY-CRM vaccine after priming with MenACWY-CRM or MenACWY-D vaccines in adolescents and adults.MethodsIn this phase IIIb, multicenter, open-label study, healthy 15–55-year-olds, who received MenACWY-CRM (N = 301) or MenACWY-D (N = 300) 4–6 years earlier or were meningococcal vaccine-naïve (N = 100), received one MenACWY-CRM vaccine dose. Immunogenicity was evaluated pre-vaccination, 3 or 5 days post-vaccination (sampling subgroups), and 28 days post-vaccination by serum bactericidal activity assay using human complement (hSBA). After vaccination, participants were monitored for 7 days for reactogenicity, 29 days for unsolicited adverse events (AEs), and 181 days for serious AEs and medically-attended AEs.ResultsSufficiency of the immune response to a MenACWY-CRM booster dose was demonstrated; the lower limit of the 1-sided 97.5% confidence interval for percentages of participants with hSBA seroresponse at 28 days post-vaccination was >75% for each serogroup in those primed with either the MenACWY-CRM or MenACWY-D vaccine. Seroresponse was observed in ≥93.24% of primed participants and ≥35.87% of naïve participants 28 days post-vaccination. At 5 days post-booster, among primed participants, hSBA titers ≥1:8 were achieved in ≥47.14% of participants for MenA and in ≥85.52% of participants for MenC, MenW and MenY, and 3.25- to 8.59-fold increases in hSBA geometric mean titers against each vaccine serogroup were observed. No safety concerns were raised throughout the 6-month follow-up period.ConclusionsA booster dose of the MenACWY-CRM vaccine induced a robust and rapid anamnestic response in adolescents and adults, irrespectively of either MenACWY-CRM or MenACWY-D vaccine administered 4–6 years earlier, with an acceptable clinical safety profile.ClinicalTrials.gov registration: NCT02986854.An Audio Summary linked to this article that can be found on Figshare https://figshare.com/articles/MenACWY-CRM_conjugate_vaccine_booster_dose_given_4_6_years_after_priming_Results_from_a_phase_IIIb_multicenter_open_label_study_in_adolescents_and_adults_mp4/11823048     

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.     

Immunogenicity and safety of 7-valent pneumococcal conjugate vaccine (PCV7) in children aged 2–5 years in China

BackgroundThe widespread use of pneumococcal conjugate vaccines (PCVs) has significantly decreased pneumococcal disease worldwide. However, China has not adopted PCVs in their national immunization schedules and had only approved these vaccines for children aged 2–15 months by 2020.MethodsIn an open-label trial, enrolled healthy children aged 2–5 years old were randomized 1:1 and divided into a 7-valent pneumococcal conjugate vaccine (PCV7) group and a Haemophilus influenzae type b conjugate vaccine (Hib) group. Children in the PCV7 group received a single dose of PCV7, and the Hib group received a single dose of Hib vaccine. Blood samples were collected before and 6 months after vaccination. Immunogenicity and safety of PCV7 were assessed at prespecified time points.ResultsSix months after a single dose of PCV7, children in the PCV7 group for all 7 serotypes, IgG mean concentrations (GMCs) and opsonophagocytic geometric mean titres (GMTs) were significantly higher (P < .001) than at baseline, and the proportion of IgG ≥ 0.35 µg/mL ranged from 90.0% to 100%. Although the antibody level increased with age, preexisting antibodies did not induce hyporesponsiveness to PCV7. In the Hib group, the antibody levels were not significantly different or had changed slightly at 6 months. PCV7 was well tolerated in all age groups, and no serious adverse events (AEs) emerged during this study.ConclusionsA single dose of PCV7 was immunogenic and safe for Chinese children aged 2–5 years, and the preexisting antibodies against the PCV7 serotypes did not change the response to vaccination. The findings supported the effectiveness of PCV7 in this age group. PCVs with broader serotype coverage are expected to expand pneumococcal disease protection.     

COVID-19 booster vaccination during pregnancy enhances maternal binding and neutralizing antibody responses and transplacental antibody transfer to the newborn

The immune response to COVID-19 booster vaccinations during pregnancy for mothers and their newborns and the functional response of vaccine-induced antibodies against Omicron variants are not well characterized. We conducted a prospective, multicenter cohort study of participants vaccinated during pregnancy with primary or booster mRNA COVID-19 vaccines from July 2021 to January 2022 at 9 academic sites. We determined SARS-CoV-2 binding and live virus and pseudovirus neutralizing antibody (nAb) titers pre- and post-vaccination, and at delivery for both maternal and infant participants. Immune responses to ancestral and Omicron BA.1 SARS-CoV-2 strains were compared between primary and booster vaccine recipients in maternal sera at delivery and in cord blood, after adjusting for days since last vaccination.A total of 240 participants received either Pfizer or Moderna mRNA vaccine during pregnancy (primary 2-dose series: 167; booster dose: 73). Booster vaccination resulted in significantly higher binding and nAb titers, including to the Omicron BA.1 variant, in maternal serum at delivery and in cord blood compared to a primary 2-dose series (range 0.44–0.88 log₁₀ higher, p < 0.0001 for all comparisons). Live virus nAb to Omicron BA.1 were present at delivery in 9 % (GMT ID50 12.7) of Pfizer and 22 % (GMT ID50 14.7) of Moderna primary series recipients, and in 73 % (GMT ID50 60.2) of mRNA boosted participants (p < 0.0001), although titers were significantly lower than to the D614G strain. Transplacental antibody transfer was efficient for all regimens with median transfer ratio range: 1.55–1.77 for IgG, 1.00–1.78 for live virus nAb and 1.79–2.36 for pseudovirus nAb. COVID-19 mRNA vaccination during pregnancy elicited robust immune responses in mothers and efficient transplacental antibody transfer to the newborn. A booster dose during pregnancy significantly increased maternal and cord blood binding and neutralizing antibody levels, including against Omicron BA.1. Findings support the use of a booster dose of COVID-19 vaccine during pregnancy.     

Incidence rates of health outcomes of interest among Chinese children exposed to selected vaccines in Yinzhou Electronic Health Records: A population-based retrospective cohort study

IntroductionOral poliovirus vaccine (OPV) and diphtheria-tetanus-acellular pertussis vaccine (DTaP) are widely used in China while Haemophilus influenzae type b vaccines (Hib) and a DTaP, inactivated poliovirus (IPV) and Hib polysaccharide conjugated to tetanus protein (PRP ~ T) combined vaccine (DTaP–IPV//PRP ~ T) have lower coverage. There are limited safety data on these vaccines in Chinese pediatric populations. Methods: To estimate incidence rates (IRs) of health outcomes of interest (HOIs) among children exposed to OPV, DTaP, Hib, and DTaP–IPV//PRP ~ T, we conducted a retrospective cohort study using a population-based electronic health record (EHR) database in Yinzhou district, Ningbo City. Children 0–2 years of age receiving at least one dose of these vaccines between January 1, 2012 and March 31, 2017 were included in the study. Yinzhou EHR database consisted of immunization records and healthcare data of children from hospitals and community health centers in the district. Eight HOIs (i.e., anaphylaxis, febrile seizures, all seizures, asthma, apnea, Kawasaki disease [KD], urticaria/angioedema, Guillain–Barré syndrome [GBS]) were identified using ICD-10 codes. Results: A total of 220,422 eligible children was identified. No cases of apnea, KD, and GBS were observed within 7 days post-vaccination. During 0–7 days post-vaccination for OPV, DTaP, Hib, and DTaP–IPV//PRP ~ T, the IRs of anaphylaxis, febrile seizures, all seizures, urticaria/angioedema and asthma ranged from 0.0 to 50.0, 0.0 to 99.9, 29.1 to 249.8, 297.8 to 949.1, and 992.7 to 2298.2 per 100,000 person-years, respectively, and 0.0 to 0.9, 0.0 to 1.9, 0.6 to 4.6, 5.6 to 17.5, and 18.7 to 42.3 per 100,000 doses, respectively. Conclusion: IRs of some HOIs in our study were comparable with those in the literature while IRs of other HOIs were not due to differences in study design, post-vaccination risk periods assessed, and vaccine types. Future studies should consider medical chart review for validating HOIs obtained in the EHR.     

A trial to evaluate the safety and immunogenicity of a 20-valent pneumococcal conjugate vaccine in populations of adults ≥65 years of age with different prior pneumococcal vaccination

IntroductionA 20-valent pneumococcal conjugate vaccine, PCV20, was developed to expand protection against vaccine-preventable pneumococcal disease. PCV20 contains the components of the 13-valent pneumococcal conjugate vaccine, PCV13, and includes capsular polysaccharide conjugates for 7 additional serotypes. Thus, PCV20 may cover those additional serotypes in individuals previously vaccinated with PCV13 or provide benefits of immunization with a conjugate vaccine to individuals previously immunized with a pneumococcal polysaccharide vaccine. This study described the safety and immunogenicity of PCV20 in adults ≥65 years of age with prior pneumococcal vaccination.MethodsThis phase 3, multicenter, randomized, open-label study was conducted in the United States and Sweden. Adults ≥65 years of age were enrolled into 1 of 3 cohorts based on their prior pneumococcal vaccination history (23-valent pneumococcal polysaccharide vaccine [PPSV23], PCV13, or both PCV13 and PPSV23). Participants were randomized 2:1 within their cohort to receive a single dose of PCV20 or PCV13 in those with prior PPSV23 only, and PCV20 or PPSV23 in those with prior PCV13 only; all participants with prior PCV13 and PPSV23 received PCV20. Safety was assessed by prompted local reactions within 10 days, systemic events within 7 days, adverse events (AEs) within 1 month, and serious AEs (SAEs) and newly diagnosed chronic medical conditions (NDCMCs) within 6 months after vaccination. Immune responses 1 month after PCV20 were assessed.ResultsThe percentages of participants reporting local reactions, systemic events, and AEs after PCV20 administration were similar across cohorts and comparable with the PCV13 and PPSV23 control groups. SAE and NDCMC rates were low in all groups. Robust immune responses, including opsonophagocytic antibody responses, to the 20 vaccine serotypes were observed 1 month after PCV20 regardless of prior pneumococcal vaccination.ConclusionsPCV20 was well tolerated and immunogenic in adults ≥65 years of age previously vaccinated with different pneumococcal vaccine regimens.Clinicaltrials.gov NCT03835975.     

Immunogenicity and safety of the RTS,S/AS01 malaria vaccine co-administered with measles,rubella and yellow fever vaccines in Ghanaian children: A phase IIIb,multi-center,non-inferiority,randomized, open,controlled trial

BackgroundTo optimize vaccine implementation visits for young children, it could be efficient to administer the first RTS,S/AS01 malaria vaccine dose during the Expanded Programme on Immunization (EPI) visit at 6 months of age together with Vitamin A supplementation and the third RTS,S/AS01 dose on the same day as yellow fever (YF), measles and rubella vaccines at 9 months of age. We evaluated the safety and immunogenicity of RTS,S/AS01 when co-administered with YF and combined measles-rubella (MR) vaccines.MethodsIn this phase 3b, open-label, controlled study (NCT02699099), 709 Ghanaian children were randomized (1:1:1) to receive RTS,S/AS01 at 6, 7.5 and 9 months of age, and YF and MR vaccines at 9 or 10.5 months of age (RTS,S coad and RTS,S alone groups, respectively). The third group received YF and MR vaccines at 9 months of age and will receive RTS,S/AS01 at 10.5, 11.5 and 12.5 months of age (Control group). All children received Vitamin A at 6 months of age. Non-inferiority of immune responses to the vaccine antigens was evaluated 1 month following co-administration versus RTS,S/AS01 or EPI vaccines (YF and MR vaccines) alone using pre-defined non-inferiority criteria. Safety was assessed until Study month 4.5.ResultsNon-inferiority of antibody responses to the anti-circumsporozoite and anti-hepatitis B virus surface antigens when RTS,S/AS01 was co-administered with YF and MR vaccines versus RTS,S/AS01 alone was demonstrated. Non-inferiority of antibody responses to the measles, rubella, and YF antigens when RTS,S/AS01 was co-administered with YF and MR vaccines versus YF and MR vaccines alone was demonstrated. The safety profile of all vaccines was clinically acceptable in all groups.ConclusionsRTS,S/AS01 can be co-administered with Vitamin A at 6 months and with YF and MR vaccines at 9 months of age during EPI visits, without immune response impairment to any vaccine antigen or negative safety effect.     

Lot-to-lot consistency,safety, tolerability,and immunogenicity of V114, a 15-valent pneumococcal conjugate vaccine,in healthy adults aged ≥50 years: A randomized phase 3 trial (PNEU-TRUE)

BackgroundOlder adults are at risk of pneumococcal disease and associated morbidity and mortality. This phase 3 study (V114-020) assessed lot-to-lot consistency across safety and immunogenicity outcomes for V114, a 15-valent pneumococcal conjugate vaccine (PCV), in healthy adults aged ≥ 50 years.MethodsAdults were randomized in a 3:3:3:1 ratio to receive a single dose of one of three lots of V114 or 13-valent PCV (PCV13), stratified by age (50–64 years, 65–74 years, and ≥ 75 years). Serotype-specific opsonophagocytic activity (OPA) and immunoglobulin G (IgG) antibodies were evaluated at baseline (Day 1) and 30 days post-vaccination. Non-serious and serious adverse events (AEs) were evaluated post-vaccination through 14 days and Month 6, respectively.ResultsOf 2340 participants enrolled, 2282 (97.5%) completed the study. Proportions of participants experiencing ≥ 1 AE were 81.0%, 77.4%, and 78.0% for V114 lots 1, 2, and 3, respectively. Comparison of V114 combined lots with PCV13 showed that proportions of participants experiencing AEs, solicited AEs, and serious AEs were comparable for both vaccines, with the exception of injection-site pain (more frequently reported with V114). OPA geometric mean titers (GMTs) and IgG geometric mean concentrations (GMCs) at 30 days post-vaccination were comparable across V114 lots, and all lots met predefined equivalence criteria for all 15 vaccine serotypes (lower and upper limits of the 95% confidence intervals of serotype-specific OPA GMT ratios for all possible pairwise comparisons across the three lots were within the equivalence margin of 0.5–2.0). Serotype-specific OPA GMTs and IgG GMCs were comparable in the V114 combined lots and PCV13 groups for the 13 shared serotypes and higher in the V114 group for serotypes unique to V114 (22F and 33F).ConclusionsV114 is well tolerated with a consistent safety profile and immune response across manufacturing lots.Clinical trials registration: NCT03950856 (www.clinicaltrials.gov); 2018-004266-33 (EudraCT).     

Comparison of the local safety of two multi-component feline vaccines,adjuvanted (1 mL) versus non-adjuvanted at reduced volume (0.5 mL), using computed tomography imaging

In 2020, a new 0.5 mL presentation of PUREVAX® RCP FeLV was registered and introduced in Europe.The objectives of this study were to investigate the local safety of this non-adjuvanted vaccine at reduced volume by classical methods (clinical examination, histopathology) and to evaluate the suitability of an alternative non-invasive methodology, the computed tomography (CT). For this purpose, the course of local reactions was assessed for 3 months after subcutaneous injection of PUREVAX® RCP FeLV 0.5 mL and compared to an adjuvanted vaccine, LEUCOFELIGEN® FeLV/RCP 1.0 mL.Injection site reactions consisted mainly of swelling reactions, which were more frequent, more pronounced and long-lasting in the adjuvanted vaccine group. Microscopically, in this group, moderate to severe inflammatory reactions were observed on day 7 (D7) and D21 post-injection and still present on D84, while mild inflammatory lesions were observed in the non-adjuvanted vaccine group only on D7 and D21. With the adjuvanted vaccine, inflamed areas were measurable by CT scan in all cats on D7 and D21, whereas they were detected only on D7 and only in 20 % of cats from the non-adjuvanted vaccine group. Besides the higher frequency, the mean inflamed volume was nearly 300 times larger in adjuvanted vaccine group on D7.Using different methodologies, the favorable safety profile of PUREVAX® RCP FeLV 0.5 mL was confirmed. Furthermore, the vaccine is aligned with current vaccination guidelines by inducing less inflammatory reactions, being adjuvant-free and injectable under a reduced volume, thus improving the convenience of administration in recommended sites (eg, legs).CT scan proved to be a suitable non-invasive method for the experimental follow-up of injection site reactions, yielding results consistent with clinical assessment and histopathology on D7 and D21. CT scan substantiated large differences between the investigated vaccines with a more prominent inflammatory reaction after injection of an adjuvanted vaccine.     

A case-crossover study of the effect of vaccination on SARS-CoV-2 transmission relevant behaviours during a period of national lockdown in England and Wales

BackgroundStudies of COVID-19 vaccine effectiveness show increases in COVID-19 cases within 14 days of a first dose, potentially reflecting post-vaccination behaviour changes associated with SARS-CoV-2 transmission before vaccine protection. However, direct evidence for a relationship between vaccination and behaviour is lacking. We aimed to examine the association between vaccination status and self-reported non-household contacts and non-essential activities during a national lockdown in England and Wales.MethodsParticipants (n = 1154) who had received the first dose of a COVID-19 vaccine reported non-household contacts and non-essential activities from February to March 2021 in monthly surveys during a national lockdown in England and Wales. We used a case-crossover study design and conditional logistic regression to examine the association between vaccination status (pre-vaccination vs 14 days post-vaccination) and self-reported contacts and activities within individuals. Stratified subgroup analyses examined potential effect heterogeneity by sociodemographic characteristics such as sex, household income or age group.Results457/1154 (39.60 %) participants reported non-household contacts post-vaccination compared with 371/1154 (32.15 %) participants pre-vaccination. 100/1154 (8.67 %) participants reported use of non-essential shops or services post-vaccination compared with 74/1154 (6.41 %) participants pre-vaccination. Post-vaccination status was associated with increased odds of reporting non-household contacts (OR 1.65, 95 % CI 1.31–2.06, p < 0.001) and use of non-essential shops or services (OR 1.50, 95 % CI 1.03–2.17, p = 0.032). This effect varied between men and women and different age groups.ConclusionParticipants had higher odds of reporting non-household contacts and use of non-essential shops or services within 14 days of their first COVID-19 vaccine compared to pre-vaccination. Public health emphasis on maintaining protective behaviours during this post-vaccination time period when individuals have yet to develop full protection from vaccination could reduce risk of SARS-CoV-2 infection.     

Impact of prior vaccination on antibody response and influenza-like illness among Australian healthcare workers after influenza vaccination in 2016

BackgroundEpidemiological studies suggest that influenza vaccine effectiveness decreases with repeated administration. We examined antibody responses to influenza vaccination among healthcare workers (HCWs) by prior vaccination history and determined the incidence of influenza infection.MethodsHCWs were vaccinated with the 2016 Southern Hemisphere quadrivalent influenza vaccine. Serum samples were collected pre-vaccination, 21–28 days and 7 months post-vaccination. Influenza antibody titres were measured at each time-point using the haemagglutination inhibition (HI) assay. Immunogenicity was compared by prior vaccination history.ResultsA total of 157 HCWs completed the study. The majority were frequently vaccinated, with only 5 reporting no prior vaccinations since 2011. Rises in titres for all vaccine strains among vaccine-naïve HCWs were significantly greater than rises observed for HCWs who received between 1 and 5 prior vaccinations (p < 0.001, respectively). Post-vaccination GMTs against influenza A but not B strains decreased as the number of prior vaccinations increased from 1 to 5. There was a significant decline in GMTs post-season for both B lineages. Sixty five (41%) HCWs reported at least one influenza-like illness episode, with 6 (4%) identified as influenza positive.ConclusionsVarying serological responses to influenza vaccination were observed among HCWs by prior vaccination history, with vaccine-naïve HCWs demonstrating greater post-vaccination responses against A(H3N2).     

Use of protective antigen of Bacillus anthracis as a model recombinant antigen to evaluate toll-like receptors 2, 3, 4, 7 and 9 agonists in mice using established functional antibody assays,antigen-specific antibody assays and cellular assays

Toll-like receptor (TLR) agonists can act as immune stimulants alone or as part of alum or oil formulations. Humoral and cellular immune responses were utilized to assess quantitative and qualitative immune response enhancement by TLR agonists using recombinant protective antigen (rPA) of B. anthracis as a model antigen. To rPA, combined with aluminum hydroxide (Alhydrogel; Al(OH)3) or squalene (AddaVax?), was added one of 7 TLR agonists: TLR2 agonist Pam3CysSK4 (PamS), TLR3 agonist double stranded polyinosinic:polycytidylic acid (PolyIC), TLR4 agonists Monophosphoryl lipid A (MPLA) or glucopyranosyl lipid A (GLA), TLR7-8 agonists 3M?052 or Resiquimod (Resiq), or TLR9 agonist CPG 7909 (CPG). CD-1 or BALB/c mice received two intraperitoneal or intramuscular immunizations 14 days apart, followed by serum or spleen sampling 14 days later. All TLR agonists except PamS induced high levels of B. anthracis lethal toxin-neutralizing antibodies and immunoglobulin G (IgG) anti-PA. Some responses were >100-fold higher than those without a TLR agonist, and IP delivery (0.5 mL) induced higher TLR-mediated antibody response increases compared to IM delivery (0.05 mL). TLR7-8 and TLR9 agonists induced profound shifts of IgG anti-PA response to IgG2a or IgG2b. Compared to the 14-day immunization schedule, use of a shortened immunization schedule of only 7 days between prime and boost found that TLR9 agonist CPG in a squalene formulation maintained higher interferon-γ-positive cells than TLR4 agonist GLA. Variability in antibody responses was lower in BALB/c mice than CD-1 mice but antibody responses were higher in CD-1 mice. Lower serum 50% effective concentration (EC50) values were found for rPA-agonist formulations and squalene formulations compared to Al(OH)3 formulations. Lower EC50 values also were associated with low frequency detection of linear peptide epitopes. In summary, TLR agonists elicited cellular immune responses and markedly boosted humoral responses.     

Immunogenicity and safety of the quadrivalent human papillomavirus vaccine in Chinese females aged 9 to 26 years: A phase 3, open-label,immunobridging study

BackgroundThe quadrivalent human papillomavirus (qHPV; HPV6/11/16/18) vaccine was approved for use in Chinese women aged 20–45 years in 2017. This Phase 3, open-label study (NCT03493542) aimed to assess immunogenicity and safety of the qHPV vaccine in Chinese girls aged 9–19 years versus Chinese young women aged 20–26 years; we report results from Day 1 through Month 7. The study will continue through Month 60 to assess antibody persistence in Chinese girls aged 9–19 years.MethodsParticipants aged 9–26 years received three doses of the qHPV vaccine (Day 1, Month 2, Month 6). Geometric mean titers (GMTs) and seroconversion percentages for anti-HPV6/11/16/18 antibodies were determined by competitive Luminex immunoassay (cLIA) in serum samples obtained on Day 1 and at Month 7. Injection-site adverse events (AEs) and systemic AEs within 30 days post-vaccination, and serious AEs (SAEs) occurring at any time during the study, were recorded.ResultsIn total, 766 participants (383 aged 9–19 years; 383 aged 20–26 years) were enrolled and received ≥1 vaccine dose. All participants in the per-protocol immunogenicity population of both age groups seroconverted to each of the vaccine HPV types at Month 7. Anti-HPV6/11/16/18 antibody GMTs at Month 7 in participants aged 9–19 years were non-inferior to those in participants aged 20–26 years. Injection-site AEs and systemic AEs were reported by 36.6% and 49.3% of 9–19-year-olds, and 40.7% and 54.8% of 20–26-year-olds, respectively. There were no vaccine-related SAEs. No participants discontinued the vaccine due to an AE and no deaths were reported.ConclusionAntibody responses induced by the 3-dose qHPV vaccination regimen in Chinese girls aged 9–19 years were non-inferior to those in Chinese young women aged 20–26 years. The vaccine was generally well tolerated in the study population.ClinicalTrials.gov Identifier: NCT03493542.     

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.     

A broad assessment of covid-19 vaccine safety using tree-based data-mining in the vaccine safety datalink

BackgroundExcept for spontaneous reporting systems, vaccine safety monitoring generally involves pre-specifying health outcomes and post-vaccination risk windows of concern. Instead, we used tree-based data-mining to look more broadly for possible adverse events after Pfizer-BioNTech, Moderna, and Janssen COVID-19 vaccination.MethodsVaccine Safety Datalink enrollees receiving ≥1 dose of COVID-19 vaccine in 2020–2021 were followed for 70 days after Pfizer-BioNTech or Moderna and 56 days after Janssen vaccination. Incident diagnoses in inpatient or emergency department settings were analyzed for clustering within both the hierarchical ICD-10-CM code structure and the post-vaccination follow-up period. We used the self-controlled tree-temporal scan statistic and TreeScan software. Monte Carlo simulation was used to estimate p-values; p = 0.01 was the pre-specified cut-off for statistical significance of a cluster.ResultsThere were 4.1, 2.6, and 0.4 million Pfizer-BioNTech, Moderna, and Janssen vaccinees, respectively. Clusters after Pfizer-BioNTech vaccination included: (1) unspecified adverse effects, (2) common vaccine reactions, such as fever, myalgia, and headache, (3) myocarditis/pericarditis, and (4) less specific cardiac or respiratory symptoms, all with the strongest clusters generally after Dose 2; and (5) COVID-19/viral pneumonia/sepsis/respiratory failure in the first 3 weeks after Dose 1. Moderna results were similar but without a significant myocarditis/pericarditis cluster. Further investigation suggested the fifth signal group was a manifestation of mRNA vaccine effectiveness after the first 3 weeks. Janssen vaccinees had clusters of unspecified or common vaccine reactions, gait/mobility abnormalities, and muscle weakness. The latter two were deemed to have arisen from confounding related to practices at one site.ConclusionsWe detected post-vaccination clusters of unspecified adverse effects, common vaccine reactions, and, for the mRNA vaccines, chest pain and palpitations, as well as myocarditis/pericarditis after Pfizer-BioNTech Dose 2. Unique advantages of this data mining are its untargeted nature and its inherent adjustment for the multiplicity of diagnoses and risk intervals scanned.