Immunogenicity and safety of the inactivated enterovirus 71 vaccine administered concomitantly with the measles-rubella vaccine in infants aged 8 months in China: A noninferiority randomized controlled trial

BackgroundTo evaluate the immunogenicity and safety of simultaneous administration of the enterovirus 71 (EV71) vaccine with the measles and rubella (MR) combined vaccine.MethodsIn this phase 4, randomized, open-label and noninferiority study, a total of 680 infants aged 8 months were enrolled and assigned to the simultaneous administration group (infants received the first dose of EV71 vaccine and MR vaccine on Day 0, and the second dose of EV71 vaccine on Day 28), or the separate administration groups (EV71 group: infants received two doses of EV71 vaccine on Day 0 and Day 28, respectively; MR group: infants received MR vaccine on Day 0). Blood sample was obtained on Day 0 and Day 56 to measure antibody responses to each of the antigens in terms of antibody titer or concentration, respectively. Local and systemic adverse reactions (ARs) and other adverse events (AEs) following each dose were monitored and compared among groups.ResultsAfter vaccination, simultaneous administration group showed similar seroconversion rates of antibody against EV71(97.9%), measles (97.4%), and rubella (94.3%) compared to EV71 group (99.6% for anti-EV71) or MR group (98.4% for anti-measles and 98.9% for anti-rubella, respectively). Noninferiority was demonstrated for all antibodies as the lower limits of two-sided 97.5% confidence intervals (CIs) of the difference in seroconversion rates between simultaneous administration group and separate administration groups were above the predefined margin of ?10%. Additionally, the adverse reaction rates were comparable among groups (54.4% in the simultaneous group versus 43.9% in the MR group versus 52.6% in the EV71 group).ConclusionAntibody responses induced by simultaneous administration of EV71 vaccine with MR vaccine were robust and noninferior to those by single administration alone. Like the previous findings by single administration alone, simultaneous administration demonstrated comparable reactogenicity and safety profiles.     

Safety and immunogenicity of a novel human Enterovirus 71 (EV71) vaccine: a randomized, placebo-controlled, double-blind, Phase I clinical trial

There is an urgent need for a novel vaccine that is effective against human Enterovirus 71 (EV71) outbreaks. A double-blind, randomized controlled study was to evaluate the safety and immunogenicity of a human EV71 vaccine in healthy adults, children and infants. The vaccine dosages were 200 U and 400 U for children and adults, and 100 U, 200 U and 400 U for infants. Subjects were randomized to receive different dosages of the vaccine or placebo. Adults received intramuscular injection on Days 0, 14 and 28. Children and Infants received on Days 0, 28 and 56. The novel human EV71 inactivated vaccine was well tolerated and highly immunogenic in healthy volunteers, especially in infant populations. For immune response, the seropositive rates (with titers ≥≥1:8) of neutralizing antibody [NTAb] increased to 100% for all dosage groups after the second vaccination. For NTAb seronegative infants before vaccination, after one dose, the NTAb GMTs were 29.7 (95% CI, 13.1-67.2), 10.1 (95% CI, 6.6-15.3), and 27.4 (95% CI, 14.3-52.2) in the 100 U, 200 U, and 400 U vaccine groups, respectively; after two doses, the GMTs were 114.1 (95% CI, 44.5-292.4), 159.5 (95% CI, 49.3-515.3), and 509.0 (95% CI, 181.3-1429.1), respectively. TRIAL REGISTRATION: ClinicalTrial.gov identifier: NCT01273246 and NCT01273233.     

A phase 2 study of the bivalent VLP norovirus vaccine candidate in older adults; impact of MPL adjuvant or a second dose

IntroductionAcute norovirus gastroenteritis causes significant morbidity and in uncommon cases fatality in older adults. We investigated the safety and immunogenicity of bivalent virus-like particle (VLP) vaccine candidate formulations with and without monophosphoryl lipid A (adjuvant MPL) in this population.MethodsIn this phase II, double-blind, controlled trial 294 healthy adults, ≥ 60 years of age, were randomized (1:1:1:1) to four groups to receive one or two intramuscular immunizations 28 days apart, with 26 18–49 year-old controls who received one MPL-free dose. One-dose groups received placebo on Day 1. Vaccine formulations contained 15 μg GI.1 and 50 μg GII.4c VLP antigens and 500 μg Al(OH)₃, with or without 15 μg MPL. We measured histo-blood group antigen blocking (HBGA) antibodies and ELISA Ig at Days 1, 8, 29, 57, 211 and 393, and avidity indices and cell-mediated immunity (CMI). Solicited local and systemic adverse events (AE) were assessed for 7 days and unsolicited AEs for 28 days after each injection.ResultsAfter one dose HBGA antibodies to both VLP antigens increased with similar kinetics and magnitude in all groups; geometric mean titres (GMTs) persisted above baseline through Day 393. GMTs were similar across age strata (18–49, 60–74, 75–84 and ≥ 85 years of age) and unaffected by a second vaccination or MPL. Total Ig showed similar responses. No clinically relevant differences or changes in avidity or CMI were observed between formulations. Both formulations were well tolerated with no vaccine-related SAEs, the most frequent AEs being mild injection site pain and fatigue.ConclusionsAdults over 60 years of age displayed no safety concerns and had similar immune responses to the norovirus VLP vaccine candidate as younger adults, unaffected by increasing age, a second dose or inclusion of MPL. This data supports the further development of the MPL-free vaccine candidate for older adults.     

Safety and immunogenicity of a single dose of a tetravalent dengue vaccine with two different serotype-2 potencies in adults in Singapore: A phase 2, double-blind,randomised, controlled trial

BackgroundEarly formulations of Takeda’s tetravalent dengue vaccine candidate (TAK-003) have demonstrated notably higher neutralizing antibody responses against serotype 2 than other serotypes. Here, we assessed the immunogenicity and tolerability in adults living in Singapore of two TAK-003 formulations: an early formulation, referred to as HD-TDV, and a new formulation with 10-fold lower serotype 2 potency, referred to as TDV (NCT02425098).MethodsSubjects aged 21–45 years were stratified by baseline dengue serostatus and randomised 1:1 to receive a single dose of either HD-TDV or TDV. Immunogenicity was evaluated at Days 15, 30, 90, 180, and 365 post-vaccination as geometric mean titres (GMTs) of neutralising antibodies and seropositivity rates. Viremia was assessed per vaccine strain. Solicited and unsolicited adverse events (AEs) were assessed by severity and causality.ResultsOf 351 subjects randomised, 176 received HD-TDV and 175 received TDV. Peak GMTs against all serotypes were observed at Day 30, with highest GMTs against DENV-2 in both groups. In subjects seronegative at baseline, the response to DENV-2 was less dominant with TDV (Day 30 GMTs: 813 for TDV, 10,966 for HD-TDV). In these subjects, DENV-4 seropositivity rates and GMTs were higher with TDV (Day 30 GMTs: 58 for TDV, 21 for HD-TDV; seropositivity rates: 76% for TDV, 60% for HD-TDV). Viremia mainly occurred for TDV-2 in both vaccine groups, with a lower incidence in TDV recipients, and mostly resolved by Day 30. Both vaccine formulations showed an acceptable safety profile with similar overall rates of solicited and unsolicited AEs across vaccine groups.ConclusionsThese results suggest a more balanced immune response with the new formulation TDV compared with the early formulation HD-TDV, particularly in subjects who were seronegative prior to vaccination, and support the choice of the new formulation for the phase 3 efficacy assessment.     

A Japanese study to assess immunogenicity and safety of a typhoid Vi polysaccharide vaccine

BackgroundAlthough typhoid fever is rare in Japan, imported cases have been reported occasionally in travelers returning from endemic areas. To achieve licensing of a typhoid Vi polysaccharide vaccine (Typhim Vi^®) and make it widely available in Japan, this study was conducted at the request of the Japanese Ministry of Health Labor and Welfare to assess the immunogenicity and safety of this vaccine when given as a single dose (the recommended schedule of administration) in a Japanese population.MethodsIn this multi-center, open-label, non-comparative, intervention study performed in Japan, 200 healthy volunteers (188 adults [≥18 years of age], 7 adolescents [12–17 years of age] and 5 children [2–11 years of age]) were administered Typhim Vi^®. Immunogenicity was assessed 28 days after vaccinations using an ELISA method of anti-Vi antibody detection. A 4-fold increase in anti-Vi titer was considered as the threshold for seroconversion for anti-Vi antibodies. Safety was assessed up to 28 days following vaccination.ResultsOverall, 92.0% (95% confidence interval [CI]: 87.3–95.4%) of participants achieved seroconversion 28 days after a single dose of typhoid Vi polysaccharide vaccine. GMTs of Vi antibody titers increased from 6.6 (95% CI: 5.8–7.4) prior to vaccination to 157.3 (95% CI: 135.1–183.2) on Day 28 after vaccination. The geometric mean of individual anti-Vi antibody titer ratios (Day 28/Day 0) was 23.9 (95% CI: 20.3–28.3). There were no immediate adverse events and no adverse events led to the discontinuation of participants from the study. Across all age groups, pain and myalgia were the most frequently reported injection site and systemic reactions, respectively. Most of these reactions were mild in intensity and resolved within 7 days.ConclusionsA single dose of typhoid Vi polysaccharide vaccine, Typhim Vi^®, demonstrated good safety and immunogenicity profile in a Japanese population.     

Interchangeability of two Enterovirus 71 inactivated vaccines in Chinese children: A phase IV,open-label,and randomized controlled trial

BackgroundIn China, three inactivated Enterovirus 71 (EV71) vaccines have been approved. Although the vaccines in an immunization series should be from a single manufacture, children sometimes have to receive EV71 vaccines from more than one manufacturers. The aim of this study was to evaluate the interchangeability and safety of vaccination with EV71 vaccines from two manufacturers among Chinese children.MethodsWe conducted an open label and randomized controlled study among children aged 6–35 months from November 2018 to January 2019. The participants were randomly assigned (1:1:1:1) to receive EV71 vaccines in one of the four different schedules (two using a single vaccine for all doses from one manufacture, and two mixed schedules using vaccines from two manufactures). Blood samples were collected pre-vaccination (Day 0) and one month after the second dose (Day 60) for neutralizing antibody assay. Immunogenicity was assessed in the per-protocol cohort and safety was assessed in the total vaccinated cohort.ResultsA total of 300 children were enrolled and randomized, of whom 89.0% (267/300) were included in the per-protocol cohort for immunogenicity analysis. The seroconversion rates of the EV71 neutralizing antibody in four groups ranged from 98.4% to 100.0%, and were not significantly different among the groups. Compared with other groups, geometric mean titer was higher in group D, in which the participants received Institute of Medical Biology Chinese Academy of Medical Sciences (CAMS) vaccine in the first dose and the Sinovac vaccine in the second dose. Safety profiles were similar among the four groups and no serious adverse events related to the vaccination were reported.ConclusionsInterchangeability of EV71 vaccines from two manufactures to complete an immunization series showed good immunogenicity and safety. The antibody response levels may vary by vaccination sequences of EV71 vaccines from the two manufacturers.Trial registration: ClinicalTrials.govNCT03873740.     

TAK − 021, an inactivated Enterovirus 71 vaccine candidate,provides cross-protection against heterologous sub-genogroups in human scavenger receptor B2 transgenic mice

BackgroundEnterovirus 71 (EV71) is a major cause of outbreaks of hand, foot and mouth disease, most frequently in children, and is a public health concern in the Asia-Pacific region. Takeda is developing TAK-021, an inactivated EV71 vaccine candidate based on sub-genogroup B2 strain MS87. In a phase I clinical trial, TAK-021 was safe, well tolerated, and immunogenic in healthy adults and elicited cross-neutralizing antibodies against heterologous EV71 sub-genogroup viruses. TAK-021 confers protection from lethal challenge with a mouse-adapted homologous strain in AG129 mice. However, it has not been determined whether TAK-021 can provide cross-protection against heterologous EV71 sub-genogroups.MethodsWe examined the efficacy of TAK-021 against challenge with EV71 sub-genogroups B4, B5, C1, C2, and C4 on day 42 (short-term) and sub-genogroups B5 and C4 on day 120 (long-term) after immunization of human scavenger receptor B2 transgenic (hSCARB2-tg) mice with TAK-021 on days 0 and 28. Antibody titers were monitored over 120 days using plaque reduction neutralization test of the homologous vaccine virus.ResultsTAK-021 elicited neutralizing antibody (nAb) in greater than 90% of the mice and nAb persisted through day 120. Challenge of control animals led to weight loss and death, as well as virus detection in various organs and histopathological lesions in the brain. All mice that received two doses of TAK-021 developed nAb and survived a short-term challenge given on day 42, while more than 80% survived a long-term challenge given on day 120. EV71 was detected less frequently and at lower levels in organs of immunized mice compared to non-immunized control mice.ConclusionsThe results show that TAK-021 can confer protection in mice against the EV71 sub-genogroups tested.     

A Phase I,randomized, open-label study to evaluate the safety and immunogenicity of an enterovirus 71 vaccine

Background

Large-scale outbreaks of enterovirus 71 (EV71) infections have occurred in Asia-Pacific regions. Severe complications include encephalitis and poliomyelitis-like paralysis, cardiopulmonary collapse, and death, necessitating an effective vaccine against EV71.

Methods

In this randomized Phase I study, we evaluated the safety and immunogenicity of an inactivated alum-adjuvanted EV71 whole-virus vaccine produced on Vero cell cultures. Sixty healthy volunteers aged 20–60 years received two doses of vaccine, administered 21 days apart. Each dose contained either 5 μg of EV71 antigen with 150 μg of adjuvant (Group A05) or 10 μg of EV71 antigen with 300 μg of adjuvant (Group B10). Serologic analysis was performed at baseline, day 21, and day 42.

Results

There were no serious adverse events. Mild injection site pain and myalgia were the most common adverse events with either vaccine formulation. The immunogenicity data showed that 90% of vaccine recipients have a 4-fold or greater increase in neutralization antibody titers (NT) after the first dose, without a further increase in NT after the second dose. The seroconversion rates on day 21 and day 42 were 86.7% and 93.1% respectively, in Group A05, and 92.9% and 96.3%, respectively, in Group B10. Thus, 5 μg and 10 μg of the EV71 vaccine can induce a remarkable immune response in healthy adults after only the first vaccination.

Conclusion

The 5 μg and 10 μg adjuvanted EV71 vaccines are generally safe and immunogenic in healthy adults. (ClinicalTrials.gov number, NCT01268787).     

Superior immunogenicity profile of the new intradermal influenza vaccine compared to the standard subcutaneous vaccine in subjects 65 years and older: A randomized controlled phase III study

BackgroundAlthough the elderly are at high risk for influenza, the immunogenicity in the elderly is lower than that in younger adults. We developed the new type of seasonal influenza vaccine with the novel intradermal (ID) injection system. In the previous exploratory phase I/II study of the ID vaccine with a dose of 15 μg HA per strain showed the superior immunogenicity profile to that of the standard subcutaneous (SC) injection vaccine in subjects aged 20 years and older.MethodsIn this multicenter, randomized, double-blind, active controlled study, 900 adults aged 65 years and older were randomized at an equal ratio to either the ID vaccine group or the licensed standard SC vaccine group. Immunogenicity was assessed using serum hemagglutination inhibition (HAI) titers. The co-primary endpoints were the geometrical mean titers (GMT) and the seroconversion rates (SCR) of HAI titers against 3 vaccine strains on Day 21 (21 days after vaccination). To evaluate the early phase immunogenicity, the GMTs and SCRs on Day 7 were also assessed in the same way as the secondary endpoints.ResultsThe superiority of the ID vaccine in the GMTs and SCRs were demonstrated in all 3 vaccine strains both on Day 7 and Day 21. The frequency of any injection-site reactions was higher in the ID vaccine group, while the severity of injection-site reactions and the frequency of systemic AEs were comparable between the ID and the SC vaccine groups.ConclusionsA single-dose of the influenza vaccine with the novel ID injection system and a dose of 15 μg HA was suggested as an appropriate regimen for clinical use in influenza prevention and associated disease burden reduction. It was also suggested that the new ID vaccine has the potential to replace the standard influenza vaccine from the view point of immunogenicity and safety.Trial registrationJAPIC Clinical Trials Information (JapicCTI-142493).     

Immunogenicity and safety of the new intradermal influenza vaccine in adults and elderly: A randomized phase 1/2 clinical trial

BackgroundRecent clinical evidence indicates that an intradermal (ID) delivery of vaccines confers superior immunogenicity as compared to a standard intramusclular or subcutaneous (SC) delivery.MethodsIn this exploratory study, 600 healthy adults were randomized to 6 study groups with subgroups of young adults (20–64 years old) and older adults (65 years and older). The subjects were either injected by a novel ID injection system with a single dose of 6, 9, or 15 μg HA or two doses (21 days apart) of 15 μg HA per strain or injected by an SC injection method with a single or two doses (21 days apart) of 15 μg HA per strain. Immunogenicity was assessed using hemagglutination inhibition (HAI) titer and microneutralization titer on Days 0, 10, 21, and 42. Solicited and unsolicited adverse events were recorded for 7 and 21 days post-vaccination, respectively.ResultsIn both young adults and older adults groups, the geometric titer (GMT) ratios of HAI in the ID 15 μg HA group were higher than those in the SC 15 μg HA group on both Day 10 and Day 21, while those in the ID 6 and ID 9 μg HA groups were comparable with those in the SC 15 μg HA group. The kinetics of GMTs of HAI suggested that the ID vaccine has the potential to induce the prompt immune response, which is rather hampered in older adults as seen in the SC vaccine groups. The injection-site AEs were generally mild and transient, and did not occur in a dose or dosage-dependent manner.ConclusionsThe results of this study clearly suggest that the immunologic profile of the ID vaccine is better than that of the SC vaccine, while the safety profile of the ID vaccine is similar to that of the SC vaccine. In this exploratory study with almost 100 subjects per each group, single or two-dose administration of the ID vaccine containing 15 μg HA was suggested to be an appropriate regimen in order to prevent influenza and to reduce the associated disease burden.Trial registrationJAPIC Clinical Trials Information (JapicCTI-132096).     

Safety,reactogenicity, and immunogenicity of Ad26.COV2.S: Results of a phase 1, randomized,double-blind,placebo-controlled COVID-19 vaccine trial in Japan

BackgroundThis study evaluated safety, reactogenicity, and immunogenicity of a 2-month homologous booster regimen of Ad26.COV2.S in Japanese adults.MethodsIn this multicenter, placebo-controlled, Phase 1 trial, adults (Cohort 1, aged 20–55 years, N = 125; Cohort 2, aged ≥ 65 years, N = 125) were randomized 2:2:1 to receive Ad26.COV2.S 5 × 10¹⁰ viral particles (vp), Ad26.COV2.S 1 × 10¹¹ vp, or placebo, followed by a homologous booster 56 days later. Safety, reactogenicity, and immunogenicity were assessed.ResultsTwo hundred participants received Ad26.COV2.S and 50 received placebo. The most frequent solicited local adverse event (AE) was vaccination-site pain, and the most frequent solicited systemic AEs were fatigue, myalgia, and headache. After primary vaccination, neutralizing and binding antibody levels increased through Day 57 (post-prime) in both cohorts. Fourteen days after boosting (Day 71), neutralizing antibody geometric mean titers (GMTs) had almost reached their peak value in Cohort 1 (5 × 10¹⁰ vp: GMT = 1049; 1 × 10¹¹ vp: GMT = 1470) and peaked in Cohort 2 (504; 651); at Day 85, GMTs had declined minimally in Cohort 2. For both cohorts, binding antibody levels peaked at Day 71 with minimal decline at Day 85.ConclusionA single dose and homologous Ad26.COV2.S booster increased antibody responses with an acceptable safety profile in Japanese adults (ClinicalTrials.gov Identifier: NCT04509947).     

Immunogenicity and safety of two-visit,intradermal pre-exposure rabies prophylaxis simultaneously administrated with chimeric live-attenuated Japanese encephalitis vaccine in children living in rabies and Japanese encephalitis endemic country

BackgroundReducing the number of doses required for pre-exposure prophylaxis (PrEP) would make it more feasible and cost-effective to implement in children at the highest risk of rabies exposure in Asia. We studied immune response of 2-site intradermal (ID) injection of rabies vaccine on days 0 and 28 for rabies PrEP simultaneously administrated with live-attenuated Japanese encephalitis chimeric virus vaccine (JE-CV) for children living in endemic area.Research design and methodsSeronegative children (n = 49) aged 12–16 months were randomized 2:1 into two groups: Group A subjects were vaccinated with 0.1-mL ID injection of purified Vero cell rabies vaccine (PVRV), each at two sites on day (D) 0 and D28; Group B subjects were vaccinated with conventional 0.5-mL intramuscular PVRV on D0, D7 and D28. Both groups received one dose of JE-CV subcutaneously on D0 and D365. Rabies virus neutralizing antibody (RVNA) titers were measured on D0, D42 and D365 after vaccination; Japanese Encephalitis (JE) neutralizing antibody titers were determined on D0, D42, D365 and D379.ResultsAll children had RVNA ≥ 0.5 IU/mL on D42 (geometric mean titers [GMTs] of RVNA 14.35 IU/mL [Group A] and 14.83 IU/mL [Group B], p > 0.05]). On D365, RVNA GMTs of subjects in group A and B were 1.50 IU/mL and 2.00 IU/mL (p > 0.05), respectively. All children had seroprotection following booster dose of JE-CV. There were no vaccine-related SAEs observed.ConclusionThe 2-site ID PrEP with PVRV on days 0 and 28 co-administrated with JE-CV are safe and immunogenic.     

Randomized,double-blind,active-controlled study evaluating the safety and immunogenicity of three vaccination schedules and two dose levels of AV7909 vaccine for anthrax post-exposure prophylaxis in healthy adults

AV7909 vaccine being developed for post-exposure prophylaxis of anthrax disease may require fewer vaccinations and reduced amount of antigen to achieve an accelerated immune response over BioThrax^® (Anthrax Vaccine Adsorbed).A phase 2, randomized, double-blind, BioThrax vacccine-controlled study was conducted to evaluate the safety and immunogenicity of three intramuscular vaccination schedules and two dose levels of AV7909 in 168 healthy adults. Subjects were randomized at a 4:3:2:4:2 ratio to 5 groups: (1) AV7909 on Days 0/14; (2) AV7909 on Days 0/28; (3) AV7909 on Days 0/14/28; (4) half dose AV7909 on Days 0/14/28; and (5) BioThrax vaccine on Days 0/14/28.Vaccinations in all groups were well tolerated. The incidences of adverse events (AEs) were 79% for AV7909 subjects and 65% for BioThrax subjects; 92% of AV7909 subjects and 87% of BioThrax subjects having AEs reported Grade 1–2 AEs. No serious AEs were assessed as potentially vaccine-related, and no AEs of potential autoimmune etiology were reported. There was no discernible pattern indicative of a safety concern across groups in the incidence or severity of reactogenicity events.Groups 2–4 achieved success for the primary endpoint, demonstrated by a lower 95% confidence limit of the percentage of subjects with protective toxin neutralizing antibody NF₅₀ values (≥0.56) to be ≥40% at Day 63. Group 1 marginally missed the criterion (lower bound 95% confidence limit of 39.5%). Immune responses were above this threshold for Groups 1, 3 and 4 at Day 28 and all groups at Day 42.Further study of an AV7909 two-dose schedule given 2 weeks apart is warranted in light of the favorable tolerability profile and immunogenicity response relative to three doses of BioThrax vaccine, as well as preliminary data from nonclinical studies indicating similar immune responses correlate with higher survival for AV7909 than BioThrax vaccine.     

Immunogenicity and safety of four different dosing regimens of anthrax vaccine adsorbed for post-exposure prophylaxis for anthrax in adults

Background

Strategies to implement post exposure prophylaxis (PEP) in case of an anthrax bioterror event are needed. To increase the number of doses of vaccine available we evaluated reducing the amount of vaccine administered at each of the vaccinations, and reducing the number of doses administered.

Methods

Healthy male and non-pregnant female subjects between the ages of 18 and 65 were enrolled and randomized 1:1:1:1 to one of four study arms to receive 0.5 mL (standard dose) of vaccine subcutaneously (SQ) at: (A) days 0, 14; (B) days 0 and 28; (C) days 0, 14, and 28; or (D) 0.25 mL at days 0, 14, and 28. A booster was provided on day 180. Safety was assessed after each dose. Blood was obtained on days 0, 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 84, 100, 180, and 201 and both Toxin Neutralizing antibody and anti-PA IgG antibody measured.

Results

Almost all subjects developed some local reactions with 46–64% reported to be of moderate severity and 3.3% severe during the primary series. Vaccine groups that included a day 14 dose induced a ≥4 fold antibody rise in more subjects on days 21, 28, and 35 than the arm without a day 14 dose. However, schedules with a full day 28 dose induced higher peak levels of antibody that persisted longer. The half dose regimen did not induce antibody as well as the full dose study arms.

Conclusion

Depending on the extent of the outbreak, effectiveness of antibiotics and availability of vaccine, the full dose 0, 28 or 0, 14, 28 schedules may have advantages.     

3~11岁儿童接种新型冠状病毒灭活疫苗的免疫原性研究

目的 评价3~11岁儿童完成新型冠状病毒（新冠病毒）疫苗基础免疫28~42 d后对原始株的免疫原性及与新冠病毒变异株的交叉免疫反应。方法 于2022年1-7月在山东省乳山市招募3~11岁已按照（0,28）d免疫程序完成2剂新冠病毒灭活疫苗基础免疫的受试者,基础免疫后28~42 d采集静脉血3 ml,检测原始株、Beta、Gamma和Delta变异株的中和抗体水平,计算中和抗体阳性率和GMT。结果 纳入免疫原性分析共395人,其中3~5岁组212人,6~11岁组183人。受试者完成基础免疫后28~42 d,血清中对原始株、Beta、Gamma和Delta变异株的中和抗体阳性率分别为100.00%、74.68%、99.24%和97.22%,年龄组间差异无统计学意义（P>0.05）。受试者完成基础疫苗后28~42 d,血清中对原始株、Beta、Gamma和Delta变异株的中和抗体GMT分别为168.19、10.51、53.65和31.10,年龄组间差异无统计学意义（P>0.05）。结论 在3~11岁儿童中接种2剂新冠病毒灭活疫苗的免疫原性良好,可对新冠病毒变异株产生一定的交叉保护。     

Immunogenicity and safety of an AS03-adjuvanted H7N1 vaccine in adults 65 years of age and older: A phase II,observer-blind,randomized, controlled trial

BackgroundH7 influenza strains can cause severe and often fatal human infections, especially in the elderly. This phase II, observer-blind, randomized trial (www.ClinicalTrials.gov: NCT01949090) assessed the immunogenicity and safety of a novel AS03-adjuvanted H7N1 vaccine that may serve as a model H7-subtype vaccine.Methods360 adults ≥65 years of age in stable health received either 1 of 4 adjuvanted A/mallard/Netherlands/12/2000 split virion vaccine formulations (3.75 μg or 7.5 μg hemagglutinin adjuvanted with either AS03_A or AS03_B) or saline placebo, given as a 2-dose series. Immunogenicity was assessed using hemagglutination-inhibition (HI) and microneutralization (MN) assays for the per-protocol cohort, comprising 332 participants at 21 days post-each dose, 332 at month 6, and 309 at month 12 (HI assay only). Safety was assessed up to month 12 for all participants who had received ≥1 dose (360 participants).ResultsFor H7N1 HI antibody assessment at day 42 (21 days post-dose 2), seroprotection rates (SPR) in the vaccinated groups were 69.6%–88.7%, seroconversion rates (SCR) 69.6%–88.5%, mean geometric increase (MGI) 11.0–18.9, and HI geometric mean titers (GMTs) 55.0–104.8. These parameters declined by month 6 and month 12. Microneutralization GMTs were 46.2–74.7 in the vaccinated groups at day 42, while vaccine response rate (VRR; proportion with ≥4-fold increase in MN titer) was 46.4%–81.5%. For the cross-reactive H7N9 strain, at day 42, HI GMT were 64.3–201.3, SPR 78.6%–96.3%, SCR 79.3%–96.3%, and MGI 14.1–37.7; MN GMTs were 44.0–85.6, and VRR 46.4–85.2%.The most frequent solicited symptom was injection site pain (41.7%–65.0% of vaccine recipients). In total, 40 participants reported 67 serious adverse events; none were considered causally related to vaccination.ConclusionsIn adults aged ≥65 years, the adjuvanted H7N1 vaccine was immunogenic after 2 doses, and had an acceptable safety profile.www.ClinicalTrials.gov: NCT01949090.     

A phase 1, randomized,placebo-controlled,dose-ranging study to evaluate the safety and immunogenicity of an mRNA-based chikungunya virus vaccine in healthy adults

BackgroundChikungunya, a mosquito-borne viral disease caused by the chikungunya virus (CHIKV), causes a significant global health burden, and there is currently no approved vaccine to prevent chikungunya disease. In this study, the safety and immunogenicity of a CHIKV mRNA vaccine candidate (mRNA-1388) were evaluated in healthy participants in a CHIKV-nonendemic region.MethodsThis phase 1, first-in-human, randomized, placebo-controlled, dose-ranging study enrolled healthy adults (ages 18–49 years) between July 2017 and March 2019 in the United States. Participants were randomly assigned (3:1) to receive 2 intramuscular injections 28 days apart with mRNA-1388 in 3 dose-level groups (25 μg, 50 μg, and 100 μg) or placebo and were followed for up to 1 year. Safety (unsolicited adverse events [AEs]), tolerability (local and systemic reactogenicity; solicited AEs), and immunogenicity (geometric mean titers [GMTs] of CHIKV neutralizing and binding antibodies) of mRNA-1388 versus placebo were evaluated.ResultsSixty participants were randomized and received ≥ 1 vaccination; 54 (90 %) completed the study. mRNA-1388 demonstrated favorable safety and reactogenicity profiles at all dose levels. Immunization with mRNA-1388 induced substantial and persistent humoral responses. Dose-dependent increases in neutralizing antibody titers were observed; GMTs (95 % confidence intervals [CIs]) at 28 days after dose 2 were 6.2 (5.1–7.6) for mRNA-1388 25 μg, 53.8 (26.8–108.1) for mRNA-1388 50 μg, 92.8 (43.6–197.6) for mRNA-1388 100 μg, and 5.0 (not estimable) for placebo. Persistent humoral responses were observed up to 1 year after vaccination and remained higher than placebo in the 2 higher mRNA-1388 dose groups. The development of CHIKV-binding antibodies followed a similar trend as that observed with neutralizing antibodies.ConclusionsmRNA-1388, the first mRNA vaccine against CHIKV, was well tolerated and elicited substantial and long-lasting neutralizing antibody responses in healthy adult participants in a nonendemic region.ClinicalTrials.gov: NCT03325075.     

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).     

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.     

Post-marketing safety surveillance for inactivated Enterovirus 71 vaccines in Jiangsu,China from 2017 to 2019

IntroductionTwo types of enterovirus 71 (EV71) vaccines, manufactured using human diploid (H2) and Vero cells, have been administered in Jiangsu Province, China since 2017. In this study, we evaluated their safety profiles using records collected from the Chinese National Adverse Events Following Immunization (AEFIs) Information System (CNAEFIS) and Electronic Immunization Registries System (EIRS) between 2017 and 2019.MethodsDemographic characteristics of the patients, AEFI incidence rates(IRs), symptoms, and time intervals were summarized from the reported AEFI data in the CNAEFIS. Also, the administered doses of the two vaccines were exported from the EIRS to calculate the IRs of AEFIs and thus compare the AEFIs between the two types of EV71 vaccines.ResultsIn total, 209, 407, and 344 AEFIs cases following EV71 vaccine administration were reported during 2017, 2018, and 2019, respectively, yielding IRs of 59.2, 48.2, and 54.2 per 100,000 doses, respectively. Fever, irritability, allergic eruptions, fatigue, loss of appetite, redness and induration at the injection site were the most commonly reported AEFIs. No significant differences in rare reactions were found between the two types of EV71 vaccinations. The majority of AEFIs were developed within 30 min to 3 days after administration.ConclusionEV71 vaccines showed satisfactory safety profiles since their first use 3 years ago in the Jiangsu Province. The AEFI profiles were identical to those in pre-marketing studies; most AEFIs after vaccination were mild and common. More active surveillance studies should be performed to provide more comprehensive post-marketing safety data.