A randomized non-inferiority clinical study to assess post-exposure prophylaxis by a new purified vero cell rabies vaccine (Rabivax-S) administered by intramuscular and intradermal routes

BackgroundRabies is a 100% fatal disease but preventable with vaccines and immunoglobulins. We have developed a new purified vero cell rabies vaccine (Rabivax-S) and evaluated its safety and immunogenicity in post-exposure prophylaxis by intramuscular (IM) and intradermal (ID) routes.MethodsThis was a randomized active-controlled non-inferiority study in 180 individuals (age 5 years and above) with suspected rabies exposure (90 each with WHO Category II and Category III exposures). The participants received either Rabivax-S (1 mL IM; five doses), Rabivax-S (0.1 mL ID; eight doses) or purified chick embryo cell vaccine (PCEC, Rabipur®) (1 mL IM; five doses). The IM doses were given on Day 0, 3, 7, 14 and 28 while the ID doses were given on days 0, 3, 7 and 28. Category III patients also received a human rabies immunoglobulin (HRIG) on Day 0. Adverse events (AEs) were recorded with diary cards till day 42. Rabies neutralizing antibody levels were measured on day 0, 7, 14, 28 and 42.ResultsIn both the category II and III patients, the geometric mean concentration (GMC) ratios of Rabivax-S IM and Rabivax-S ID groups to PCEC IM were more than 1, thus proving the non-inferiority. GMCs were similar or higher in Rabivax-S groups at all the time points. Seroresponse against rabies (RFFIT titre ⩾ 0.5 IU/mL) was achieved in all participants. Mostly mild local and systemic adverse events were reported across the three groups and all resolved without sequelae.ConclusionsRabivax-S was well tolerated and showed immunogenicity comparable to a licensed rabies vaccine by both IM and ID routes in post-exposure prophylaxis.Registry No.: CTRI/2012/11/003135     

A phase 1, open-label,randomized study to compare the immunogenicity and safety of different administration routes and doses of virosomal influenza vaccine in elderly

BackgroundInfluenza remains a significant problem in elderly despite widespread vaccination coverage. This randomized, phase-I study in elderly compared different strategies of improving vaccine immunogenicity.MethodsA total of 370 healthy participants (⩾65 years) were randomized equally 1:1:1:1:1:1 to six influenza vaccine treatments (approximately 60–63 participants per treatment arm) at day 1 that consisted of three investigational virosomal vaccine formulations at doses of 7.5, 15, and 45 μg HA antigen/strain administered intradermally (ID) by MicronJet600™ microneedle device (NanoPass Technologies) or intramuscularly (IM), and three comparator registered seasonal vaccines; Inflexal V™ (Janssen) and MF59 adjuvanted Fluad™ (Novartis) administered IM and Intanza™ (Sanofi Pasteur) administered ID via Soluvia™ prefilled microinjection system (BD). Serological evaluations were performed at days 22 and 90 and safety followed-up for 6 months.ResultsIntradermal delivery of virosomal vaccine using MicronJet600™ resulted in significantly higher immunogenicity than the equivalent dose of virosomal Inflexal V™ administered intramuscularly across most of the parameters and strains, as well as in some of the readouts and strains as compared with the 45 μg dose of virosomal vaccine formulation. Of 370 participants, 300 (81.1%) reported ⩾1 adverse event (AE); more participants reported solicited local AEs (72.2%) than solicited systemic AEs (12.2%).ConclusionsIntradermal delivery significantly improved influenza vaccine immunogenicity compared with intramuscular delivery. Triple dose (45 μg) virosomal vaccine did not demonstrate any benefit on vaccine’s immunogenicity over 15 μg commercial presentation. All treatments were generally safe and well-tolerated.     

Estimated protective effectiveness of intramuscular immune serum globulin post-exposure prophylaxis during a measles outbreak in British Columbia,Canada, 2014

IntroductionIntramuscular Immune Serum Globulin (IM ISG) is recommended as post-measles exposure prophylaxis (PEP) when administered within 6 days of initial exposure, with variable effectiveness in preventing measles disease. Effectiveness of IM ISG PEP in preventing clinical measles was assessed during a 2014 measles outbreak among a religious-affiliated community in British Columbia, Canada.Material and methodsFifty-five self-reporting measles susceptible contacts were offered exclusively IM ISG PEP within an eligibility period best surmised to be within 6 days of initial measles case exposure. Clinical outcome of IM ISG PEP recipients was determined by selective active surveillance and case self-reporting. IM ISG PEP failure was defined as onset of a measles-like rash 8–21 days post-IM ISG PEP. Post-IM ISG PEP measles IgG antibody level was tested in 8 recipients. Factors associated with measles disease were analyzed.ResultsSeventeen of 55 IM ISG PEP recipients developed clinically consistent measles in the following 8–21 days, corresponding to an estimated crude protective effectiveness of 69%. In school aged children 5–18 years, among whom potential exposure intensity and immune status confounders were considered less likely, estimated IM ISG PEP protective effectiveness was 50%. Age <25 years was significantly associated with breakthrough clinical measles in bivariate analysis (p = 0.0217). Among 8 tested contacts of 17 considered IM ISG PEP failures, post-IM ISG PEP measles IgG antibody levels (mean 16.3 days (range 16–17 days) post-PEP) were all <150 mIU/ml.ConclusionsThe estimated crude IM ISG PEP protective effectiveness against measles disease within 8–21 days post-ISG administration was 69%. Accuracy of this estimated protective effectiveness is vulnerable to assumptions and uncertainties in ascertaining exposure details and pre-exposure immune status. Increasing the Canadian recommended measles IM ISG PEP dose from 0.25 to 0.5 ml/kg (up to 15 ml maximum volume) may increase protective effectiveness.     

A systematic review and meta-analysis of management options for adults who respond poorly to hepatitis B vaccination

An estimated 5–10% of adults do not seroconvert after a three-dose primary course of hepatitis B vaccines, and are considered non-responders. Many approaches have been used to induce immunity in healthy adult non-responders, but few studies have compared their relative effectiveness. We conducted a systematic review and meta-analysis of seroconversion rates after additional doses of four approaches: 20 mcg or 40 mcg intramuscular (IM), and 5 mcg or 20 mcg intradermal (ID). The search identified 13 articles encompassing 16 studies (N = 1067) that met the eligibility criteria. Seroconversion rates after additional doses of each approach were pooled and estimated. After one additional dose, the four approaches produced very similar seroconversion rates and we did not find any evidence to support the use of 40 mcg IM in healthy adults.     

Immunogenicity and safety of the inactivated Japanese encephalitis vaccine IXIARO® in elderly subjects: Open-label,uncontrolled, multi-center,phase 4 study

BackgroundIXIARO® is a Vero cell-derived, inactivated Japanese encephalitis (JE) vaccine licensed mainly in western countries for children and adults traveling to JE endemic areas. Limited immunogenicity and safety data in elderly travelers have been available.ObjectivesTo evaluate safety and immunogenicity of IXIARO in elderly subjects.MethodsOpen-label, single arm, multi-centered study. Two-hundred subjects with good general health, including adequately controlled chronic conditions, received two doses of IXIARO®, 28 days apart. Protective levels of antibodies were tested 42 days after the second dose. Systemic and local adverse events (AEs) were solicited for 7 days after each dose, unsolicited AEs were collected up to day 70 and in a phone call at month 7.Summary of resultsSubjects were aged 64–83 years (median 69.0 years). Nineteen percent of subjects had serious or medically attended AEs up to Day 70 (primary endpoint), none of them causally linked to IXIARO. Solicited local AEs were reported by 33.5% (most common: local tenderness) and solicited systemic AEs by 27% (most common: headache) of subjects. The seroprotection rate was 65% with a geometric mean titre (GMT) of 37. Subjects with tick borne encephalitis (TBE) vaccinations in the past 5 years (N = 29) had a SCR of 90% and GMT of 65.ConclusionsIXIARO is generally well tolerated in the elderly, and the safety profile is largely comparable with younger adults. SCR and GMT are lower compared to younger adults, but SCR is in the range reported in elderly for other vaccines e.g. against TBE, hepatitis-A virus (HAV)/hepatitis-B virus (HBV), influenza. The differences in SCR and GMT from younger to elderly adults were in the range of other vaccines.Duration of protection is uncertain in older persons, therefore a booster dose (third dose) should be considered before any further exposure to JE virus.     

A Phase 2 randomized,observer-blind,placebo-controlled,dose-ranging trial of aluminum-adjuvanted respiratory syncytial virus F particle vaccine formulations in healthy women of childbearing age

ObjectiveRespiratory syncytial virus (RSV) causes significant morbidity and mortality in infants. We are developing an RSV fusion (F) protein nanoparticle vaccine for immunization of third trimester pregnant women to passively protect infants through transfer of RSV-specific maternal antibodies. The present trial was performed to assess the immunogenicity and safety of several formulations of RSV F vaccine in 1-dose or 2-dose schedules.MethodsPlacebo, or vaccine with 60 μg or 120 μg RSV F protein and 0.2, 0.4, or 0.8 mg aluminum, were administered intramuscularly on Days 0 and 28 to healthy women 18–35 years old. Immunogenicity was assessed from Days 0 through 91 based on anti-F IgG and palivizumab-competitive antibody (PCA) by ELISA, and RSV A and B neutralizing antibodies by microneutralization (MN) assay. Solicited adverse events were collected through Day 7 and unsolicited adverse events through Day 91.ResultsAll formulations were well-tolerated, with no treatment-related serious adverse events. Anti-F IgG and PCA responses were correlated and increased after both doses, while MN increased significantly only after the first dose, then plateaued. The timeliest and most robust antibody responses followed one dose of 120 μg RSV F protein and 0.4 mg aluminum, but persistence through 91 days was modestly (∼25%) superior following two doses of 60 μg RSV F protein and 0.8 mg aluminum. Western blot analysis showed RSV infections in active vaccinees were reduced by 52% overall (p = 0.009 overall) over the Day 0 through 90 period.ConclusionsRSV F nanoparticle vaccine formulations were well tolerated and immunogenic. The optimal combination of convenience and rapid response for immunization in the third trimester occurred with 120 μg RSV F and 0.4 mg aluminum, which achieved peak immune responses in 14 days and sufficient persistence through 91 days to allow for passive transfer of IgG antibodies to the fetus. NCT01960686.     

Safety and immunogenicity of a novel multiple antigen pneumococcal vaccine in adults: A Phase 1 randomised clinical trial

BackgroundPneumococcal vaccines, combining multiple protein antigens, provide an alternative approach to currently marketed vaccines and may provide broader protection against pneumococcal disease. This trial evaluated the safety and immunogenicity of a novel vaccine candidate PnuBioVax in healthy young adults.MethodsIn a Phase 1 double-blind study, 36 subjects (18–40 years) were randomised to receive 3 doses of PnuBioVax, 28 days apart, at one of three dose levels (50, 200, 500 µg) or placebo. Safety assessments included rates of emergent adverse events (AEs), injection site and systemic reactions. Immunogenicity endpoints included antibody titre against PnuBioVax and selected pneumococcal antigens.ResultsIn the placebo (n = 9) and PnuBioVax (n = 27) vaccinated subjects, there were 15 and 72, reported TEAEs, respectively. The majority of TEAEs were classified as common vaccine related AEs. There were no serious AEs. Common vaccine-related AEs occurred in 13 PnuBioVax (48%) and 2 placebo (22%) subjects and were all headaches (mild and moderate). Injection site reactions, mostly pain and tenderness (graded mild or moderate) were reported, in particular in the 200 µg and 500 µg PnuBioVax groups. There were no clinically significant changes in vital signs, ECG or blood chemistries. Subjects receiving the higher dose (200 and 500 μg) demonstrated a greater fold increase in IgG titre compared with the starting dose (50 μg) or the placebo group. The fold-increase was statistically significantly higher for 200 and 500 µg PnuBioVax vs 50 µg PnuBioVax and placebo at each timepoint post-immunisation. Most subjects receiving 200 and 500 µg PnuBioVax demonstrated a ≥2-fold increase in antibody against pneumolysin (Ply), Pneumococcal surface antigen (PsaA), PiaA (Pneumococcal iron acquisition), PspA (Pneumococcal surface protein A) and pilus proteins (RrgB and RrgA).ConclusionsAll dose levels were considered safe and well tolerated. There was a statistically significant increase in anti-PnuBioVax IgG titres at the 200 and 500 µg dose levels compared to 50 µg and placebo. Trial registration number: NCT02572635 https://www.clinicaltrials.gov.     

Evaluation of anthrax vaccine safety in 18 to 20 year olds: A first step towards age de-escalation studies in adolescents

Background/objectivesAnthrax vaccine adsorbed (AVA, BioThrax^®) is recommended for post-exposure prophylaxis administration for the US population in response to large-scale Bacillus anthracis spore exposure. However, no information exists on AVA use in children and ethical barriers exist to performing pre-event pediatric AVA studies. A Presidential Ethics Commission proposed a potential pathway for such studies utilizing an age de-escalation process comparing safety and immunogenicity data from 18 to 20 year-olds to older adults and if acceptable proceeding to evaluations in younger adolescents. We conducted exploratory summary re-analyses of existing databases from 18 to 20 year-olds (n = 74) compared to adults aged 21 to 29 years (n = 243) who participated in four previous US government funded AVA studies.MethodsData extracted from studies included elicited local injection-site and systemic adverse events (AEs) following AVA doses given subcutaneously at 0, 2, and 4 weeks. Additionally, proportions of subjects with ≥4-fold antibody rises from baseline to post-second and post-third AVA doses (seroresponse) were obtained.ResultsRates of any elicited local AEs were not significantly different between younger and older age groups for local events (79.2% vs. 83.8%, P = 0.120) or systemic events (45.4% vs. 50.5%, P = 0.188). Robust and similar proportions of seroresponses to vaccination were observed in both age groups.ConclusionsAVA was safe and immunogenic in 18 to 20 year-olds compared to 21 to 29 year-olds. These results provide initial information to anthrax and pediatric specialists if AVA studies in adolescents are required.     

Safety,immunogenicity and dose response of VLA84, a new vaccine candidate against Clostridium difficile,in healthy volunteers

BackgroundClostridium difficile infection (CDI) is the leading cause of antibiotic-associated diarrhoea and colitis and the most common pathogen of health care-associated infections. In the US, CDI causes approximately half a million infections and close to 30,000 deaths. Despite antibiotic treatment of C. difficile associated diarrhoea, the disease is complicated by its recurrence in up to 30% of patients.MethodsAn open-label, partially randomized, dose-escalation Phase I trial was performed in two parts. Sixty volunteers aged ≥18 to <65 years were randomized into five treatment groups to receive three immunizations (Day 0, 7, 21) of VLA84 (20 μg with Alum, 75 μg with or without Alum, 200 μg with or without Alum). Eighty-one volunteers aged ≥65 were randomized into four treatment groups (75 μg with or without Alum, 200 μg with or without Alum) and received four immunizations (Day 0, 7, 28 and 56). All subjects were followed for safety and immunogenicity for six months.ResultsVLA84 was safe and well tolerated. Fifty-one adult volunteers (85%) and 50 elderly (62%) experienced at least one solicited or unsolicited adverse event (AE). Forty-eight adult volunteers (80%) and 40 elderly (49%) experienced related AEs which were mostly mild or moderate. No related serious adverse event and no death occurred. The vaccine induced high antibody titres against Toxin A and Toxin B in both study populations.ConclusionVLA84 was safe, well tolerated and highly immunogenic in adult volunteers aged ≥18 to <65 years and elderly volunteers aged ≥65 years.This study is registered at ClinicalTrials.gov under registration number NCT01296386.     

Efficacy and safety of a pentavalent live human-bovine reassortant rotavirus vaccine (RV5) in healthy Chinese infants: A randomized,double-blind,placebo-controlled trial

BackgroundA randomized, double-blind, placebo-controlled multicenter trial was conducted in healthy Chinese infants to assess the efficacy and safety of a pentavalent live human-bovine reassortant rotavirus vaccine (RotaTeq™, RV5) against rotavirus gastroenteritis (RVGE).Methods4040 participants aged 6–12 weeks were enrolled and randomly assigned to either 3 oral doses of RV5 (n = 2020) or placebo (n = 2020), administered ∼4 weeks apart. The participants also received OPV and DTaP in a concomitant or staggered fashion. The primary objective was to evaluate vaccine efficacy (VE) against naturally-occurring RVGE at least 14 days following the third dose. Key secondary objectives included: VE against naturally-occurring severe RVGE and VE against severe and any-severity RVGE caused by rotavirus serotypes contained in the vaccine, occurring at least 14 days after the third dose. All adverse events (AEs) were collected for 30 days following each dose. Serious AEs (SAEs) and intussusception cases were collected during the entire study. (ClinicalTrials.gov registry: NCT02062385).ResultsVE against RVGE of any-severity caused by any serotype was 69.3% (95% CI: 54.5, 79.7). The secondary efficacy analysis showed an efficacy of: 78.9% (95% CI: 59.1, 90.1) against severe RVGE caused by any serotype; 69.9% (95% CI: 55.2, 80.3) and 78.9% (95% CI: 59.1, 90.1) against any-severity and severe RVGE caused by serotypes contained in the vaccine, respectively. Within 30 days following any vaccination, 53.5% (1079/2015) and 53.3% (1077/2019) of participants reported at least one AE, and 5.8% (116/2015) and 5.7% (116/2019) reported SAEs in the vaccine and placebo groups, respectively. No SAEs were considered vaccine-related in recipients of RV5. Two intussusception cases were reported in recipients of RV5 who recovered after receiving treatment. Neither was considered vaccine-related.ConclusionsIn Chinese infants, RV5 was efficacious against any-severity and severe RVGE caused by any serotype and generally well-tolerated with respect to AEs.     

Immunogenicity and safety of zoster vaccine live administered with quadrivalent influenza virus vaccine

ObjectivesRandomized, blinded, placebo-controlled trial to evaluate the safety and immunogenicity of ZOSTAVAX™ (ZV) administered concomitantly with quadrivalent inactivated influenza vaccine (IIV4) in adults ≥ 50 years of age (NCT02519855).MethodsOverall, 440 participants were randomized into the Concomitant Group (CG) and 442 into the Sequential Group (SG). The CG received ZV and IIV4 at separate injection sites on Day 1 and matching placebo at Week 4. The SG received placebo and IIV4 (2015–2016 influenza season) at separate injection sites on Day 1 and ZV at Week 4.Immunogenicity endpointsVaricella-zoster virus (VZV) antibody geometric mean titer (GMT) and geometric mean fold-rise (GMFR) from baseline to 4 weeks postvaccination, measured by glycoprotein enzyme-linked immunosorbent assay (gpELISA) and adjusted for age and prevaccination titer. Influenza strain-specific GMT at baseline and 4 weeks postvaccination was measured by hemagglutination inhibition (HAI) assay.Safety endpointsInjection-site and systemic adverse experiences (AEs) within 28 days following any vaccination and serious AEs throughout the study.ResultsThe adjusted VZV antibody GMT ratio (CG/SG) was 0.87 (95%CI: 0.80, 0.95), meeting the prespecified noninferiority criterion. The VZV antibody GMFR in the CG was 1.9 (95%CI: 1.76, 2.05), meeting the acceptability criterion. Influenza antibody GMT ratios for A/H1N1, A/H3N2, B/Yamagata and B/Victoria were 1.02 (95%CI: 0.88, 1.18), 1.10 (95%CI: 0.94, 1.29), 1.00 (95%CI: 0.88, 1.14), and 0.99 (95%CI: 0.87, 1.13), respectively. The frequency of vaccine-related injection-site and systemic AEs was comparable between groups. No vaccine-related serious AE was observed.ConclusionThe concomitant administration of ZV and IIV4 to adults ≥ 50 years of age induced VZV-specific and influenza-specific antibody responses that were comparable to those following administration of either vaccine alone, and was generally well tolerated.     

Lot-to-lot consistency,safety and immunogenicity of 3 lots of Haemophilus influenzae type b conjugate vaccine: results from a phase III randomized,multicenter study in infants

BackgroundVaccination against Haemophilus influenzae type b (Hib) is included in routine pediatric immunization schedule in the United States. Previous vaccine shortages have created the need for additional options for Hib vaccination.MethodsThis phase III, randomized, multi-centered study (NCT01000974) evaluated the safety and immunogenicity of a monovalent tetanus toxoid-conjugate Hib vaccine (Hib-TT) compared to a monovalent (Hib-TT control) and a combination Hib-TT vaccine. We hierarchically assessed lot-to-lot consistency of 3 Hib-TT lots and non-inferiority of Hib-TT to Hib-TT control. We co-administered routine pediatric vaccines with Hib-TT vaccines at 2, 4, 6 months (primary vaccination) and 15–18 months of age (booster vaccination). We recorded adverse events (AEs) for 4 (solicited) and 31 days (unsolicited) post-vaccination and serious AEs (SAEs) throughout the study.ResultsOf 4009 enrolled children, 3086 completed booster phase. Lot-to-lot consistency was not demonstrated. The study met statistical criteria for non-inferiority of Hib-TT to Hib-TT control in terms of immune responses to Hib and co-administered vaccines’ antigens, but not in terms of participants achieving post-primary vaccination anti-PRP levels ≥1 µg/mL. Because of the hierarchical nature of the objectives, non-inferiority could not be established. In all groups, 92.5–96.7% and 99.6–100% of participants achieved anti-PRP levels ≥0.15 µg/mL, while 78.3–89.8% and 97.9–99.1% had anti-PRP levels ≥1 µg/mL, post-primary and post-booster vaccination, respectively. Immune responses to co-administered vaccines and reported incidence of AEs were comparable among groups. We recorded SAEs for 107/2963 (3.6%), 24/520 (4.6%), and 21/520 (4.0%) children post-primary vaccination, and 29/2337 (1.2%), 4/435 (0.9%), and 2/400 (0.5%) children post-booster vaccination with Hib-TT, Hib-TT control and combination Hib-TT vaccine, respectively; 6/5330 (0.1%) SAEs in the Hib-TT groups were considered vaccine-related.ConclusionHib-TT induced seroprotective antibody concentrations in the majority of participants and was well-tolerated when co-administered with routine pediatric vaccines according to a 3 + 1 schedule.     

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.     

Safety and immunogenicity of a mutagenized,live attenuated Rift Valley fever vaccine,MP-12, in a Phase 1 dose escalation and route comparison study in humans

Rift Valley fever (RVF) poses a risk as a potential agent in bioterrorism or agroterrorism. A live attenuated RVF vaccine (RVF MP-12) has been shown to be safe and protective in animals and showed promise in two initial clinical trials. In the present study, healthy adult human volunteers (N = 56) received a single injection of (a) RVF MP-12, administered subcutaneously (SQ) at a concentration of 10^4.7 plaque-forming units (pfu) (SQ Group); (b) RVF MP-12, administered intramuscularly (IM) at 10^3.4 pfu (IM Group 1); (c) RVF MP-12, administered IM at 10^4.4 pfu (IM Group 2); or (d) saline (Placebo Group). The vaccine was well tolerated by volunteers in all dose and route groups. Infrequent and minor adverse events were seen among recipients of both placebo and RVF MP-12. One subject had viremia detectable by direct plaque assay, and six subjects from IM Group 2 had transient low-titer viremia detectable only by nucleic acid amplification. Of the 43 vaccine recipients, 40 (93%) achieved neutralizing antibodies (measured as an 80% plaque reduction neutralization titer [PRNT₈₀]) as well as RVF-specific IgM and IgG. The highest peak geometric mean PRNT₈₀ titers were observed in IM Group 2. Of 34 RVF MP-12 recipients available for testing 1 year following inoculation, 28 (82%) remained seropositive (PRNT₈₀ ≥ 1:20); this included 20 of 23 vaccinees (87%) from IM Group 2. The live attenuated RVF MP-12 vaccine was safe and immunogenic at the doses and routes studied. Given the need for an effective vaccine against RVF virus, further evaluation in humans is warranted.     

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).     

Safety,tolerability, and immunogenicity of 7-valent pneumococcal conjugate vaccine in older infants and young children in China who are naive to pneumococcal vaccination: Results of a phase 4 open-label trial

BackgroundThis postlicensure study was conducted to assess immunogenicity and safety of PCV7 catch-up regimens in previously unvaccinated older infants and young children in China.MethodsHealthy children 121 days to <72 months were grouped by age and immunized with 1 of 4 PCV7 dosing regimens. Serotype-specific IgG geometric mean concentrations (GMCs) and percentage of subjects with IgG ≥ 0.35 μg/mL were assessed before vaccination and 1 and 12 months postvaccination. The incidence of clinically important adverse events (AEs) and serious AEs (SAEs), AEs leading to study withdrawal, and protocol-related AEs were assessed throughout the study.ResultsPrevaccination serotype-specific GMCs were generally low in subjects <24 months; the majority of children 24 to <72 months had IgG concentrations ≥0.35 μg/mL. One month postvaccination, GMCs were similar across groups for the 7 PCV serotypes, ranging from 3.95 to 13.02 μg/mL; the highest antibody levels were observed for serotype 14. Regardless of dosing regimen, >90% of subjects had IgG ≥ 0.35 μg/mL for each PCV serotype. At 12-month follow-up, IgG GMCs ranged from 0.65 to 5.19, and all remained above prevaccination IgG GMC; >70% of subjects had IgG ≥ 0.35 μg/mL. Older children generally had the most robust immune response both at 1 month postvaccination and during 12-month follow-up. PCV7 was well tolerated. Pyrexia, which was mild to moderate in severity, was the most common AE. Two subjects reported SAEs (n = 4), and there was 1 study withdrawal; none of these were considered treatment related.ConclusionIn China, PCV7 catch-up vaccinations given to older infants and young children naive to pneumococcal vaccines resulted in a robust immune response to all serotypes; this response persisted after 1 year. PCV7 was well tolerated in Chinese infants and children.     

Revaccination with 23-valent pneumococcal polysaccharide vaccine in the Japanese elderly is well tolerated and elicits immune responses

BackgroundFollowing primary vaccination of adults ⩾65 years of age with 23-valent pneumococcal polysaccharide vaccine (PPSV23), immune responses increase and thereafter appear to decrease over time. With increased life expectancy worldwide, revaccination with PPSV23 may be required for continued protection of the elderly population against pneumococcal disease. The present study evaluated the immunogenicity and safety of revaccination with PPSV23 in the Japanese elderly.MethodsDepending on prior history of PPSV23 vaccination, adults aged ⩾70 years were given a first dose (primary group; N = 81) or second dose (revaccination group; N = 161, at least 5 years after first dose) of PPSV23 intramuscularly. Subjects were matched for gender, age, and number and type of comorbidity across both groups. Blood samples were collected before and 4 weeks postvaccination to measure serotype-specific immunoglobulin G (IgG) concentrations and opsonophagocytic killing activity (OPA) antibody titers to serotypes included in the vaccine. Injection-site and systemic adverse events (AEs) were collected for 14 days postvaccination.ResultsBaseline serotype-specific IgG geometric mean concentrations (GMCs) and OPA geometric mean titers (GMTs) were generally higher in subjects with a prior history of PPSV23 vaccination than in PPSV23-naïve subjects. The levels of IgG GMCs and OPA GMTs after revaccination were generally comparable to those observed after primary vaccination. Incidences of systemic AEs were comparable between the 2 groups. Although incidences of injection-site AEs were higher following revaccination than primary vaccination, the difference was not clinically significant as most AEs were mild to moderate in intensity and resolved within 5 days after revaccination without treatment.ConclusionRevaccination with PPSV23 was well tolerated and associated with increases in serotype-specific IgG concentrations and OPA titers in the elderly who received a prior PPSV23 dose at least 5 years before. Revaccination with PPSV23 can be safely implemented in the elderly for continued prevention against pneumococcal disease.Clinical trial registry number: NCT02260882     

Safety,tolerability, and immunogenicity of a single dose 4-antigen or 3-antigen Staphylococcus aureus vaccine in healthy older adults: Results of a randomised trial

BackgroundThe decline in immune function with age is a challenge to vaccine development. Following an initial study in adults aged 18–64 years, this study evaluated the safety and immunogenicity of Staphylococcus aureus (S. aureus) 4-antigen (SA4Ag) and 3-antigen (SA3Ag) vaccine in older adults. SA3Ag included capsular polysaccharide serotypes 5 and 8 (CP5 and CP8) conjugated to the nontoxic mutant form of diphtheria toxin (CRM₁₉₇) and a recombinant version of clumping factor A (ClfA). SA4Ag included these antigens, with the addition of a recombinant manganese transporter C (rP305A or MntC). Both vaccines were unadjuvanted.MethodsIn this double-blind, sponsor-unblinded, placebo-controlled, phase 1/2 study, 284 healthy adults (aged 65–85 years) were randomised to receive a single dose of one of three formulations of SA4Ag with escalating dose levels of rP305A, SA3Ag, or placebo. Functional immune responses were measured using opsonophagocytic activity (OPA) killing and fibrinogen-binding inhibition (FBI) assays; immunogenicity was also assessed using a competitive Luminex® immunoassay (cLIA). T-cell responses were measured in a small subgroup of subjects using intracellular cytokine staining (ICS) assays.ResultsThe results demonstrated rapid and robust functional immune responses to all antigens in healthy older adults. A high proportion of active vaccine recipients met the pre-defined antibody thresholds for each antigen at Day 29. SA4Ag elicited a dose-level response to rP305A with up to a 13-fold rise in cLIA titres at Day 29. Opsonophagocytic activity (OPA) assays showed >50- and >20-fold rises in functional titres using S. aureus strains expressing CP5 and CP8, respectively, at Day 29. T-cell cytokine responses were not substantially above background levels. There were no safety concerns in this study population and no increases in adverse events with higher rP305A dose levels.ConclusionsSingle-dose vaccination of SA4Ag and SA3Ag in healthy adults aged 65–85 years safely induced rapid and robust functional immune responses, supporting further development of SA4Ag for the prevention of S. aureus disease in adults up to age 85 years. Trial registration number: NCT01643941.     

Immunogenicity after pre- and post-exposure rabies vaccination: A systematic review and dose-response meta-analysis

BackgroundThere are a myriad of vaccine schedules for rabies pre- (PrEP) and post-exposure prophylaxis (PEP) that differ in the number and time doses, number of visits, length of schedule, and route of administration. The objective of this study was to systematically review the evidence and investigate how the differences in schedules influence titres over time.MethodsFour databases were searched from inception to January 2020 for rabies PrEP and PEP studies. A dose–response meta-analysis was utilised to pool geometric mean titres (GMT) over time. Subgroup analyses by route of administration, age group, and schedule were conducted.Results80 studies met the inclusion criteria and contributed with 191 datasets and 12,413 participants. Both intradermal (ID) and intramuscular (IM) PrEP/PEP produce adequate GMTs. Significantly lower GMT levels were achieved in older (>50yrs) compared to younger (<50yrs) participants. Short 1-week schedules were as effective as longer schedules that can take between 3 and 12 weeks to complete.ConclusionsSeveral effective ID and IM schedules were identified, the selection of a schedule should take into account the patient’s needs, costs, availability to return for subsequent doses, and the time required to complete the schedule. Older individuals warrant special attention as they develop lower antibody response.     

Cross-species prediction of human survival probabilities for accelerated anthrax vaccine absorbed (AVA) regimens and the potential for vaccine and antibiotic dose sparing

Anthrax vaccine adsorbed (AVA, BioThrax) was recently approved by the Food and Drug Administration (FDA) for a post-exposure prophylaxis (PEP) indication in adults 18–65 years of age. The schedule is three doses administered subcutaneous (SC) at 2-week intervals (0, 2, and 4 weeks), in conjunction with a 60-day course of antimicrobials. The Public Health Emergency Medical Countermeasures Enterprise (PHEMCE) developed an animal model to support assessment of a shortened antimicrobial PEP duration following Bacillus anthracis exposure. A nonhuman primate (NHP) study was completed to evaluate the efficacy of a two dose anthrax vaccine absorbed (AVA) schedule (0, 2 weeks) aerosol challenged with high levels of B. anthracis spores at week 4– the time point at which humans would receive the third vaccination of the approved PEP schedule. Here we use logistic regression models to combine the survival data from the NHP study along with serum anthrax lethal toxin neutralizing activity (TNA) and anti-PA IgG measured by enzyme linked immunosorbent assay (ELISA) data to perform a cross-species analysis to estimate survival probabilities in vaccinated human populations at this time interval (week 4 of the PEP schedule). The bridging analysis demonstrated that high levels of NHP protection also yield high predicted probability of human survival just 2 weeks after the second dose of vaccine with the full or half antigen dose regimen. The absolute difference in probability of human survival between the full and half antigen dose was estimated to be at most approximately 20%, indicating that more investigation of the half-antigen dose for vaccine dose sparing strategies may be warranted.