Barriers to early uptake of tetanus, diphtheria and acellular pertussis vaccine (Tdap) among adults-United States, 2005-2007

Background

The tetanus, diphtheria and acellular pertussis vaccine (Tdap) was recommended by the Advisory Committee on Immunization Practices (ACIP) for U.S. adults in 2005. Our objective was to identify barriers to early uptake of Tdap among adult populations.

Methods

The 2007 National Immunization Survey (NIS)-Adult was a telephone survey sponsored by the Centers for Disease Control and Prevention (CDC). Immunization information was collected for persons aged ≥18 years on all ACIP-recommended vaccines. A weighted analysis accounted for the complex survey design and non-response.

Results

Overall, 3.6% of adults aged 18-64 years reported receipt of a Tdap vaccination. Of unvaccinated respondents, 18.8% had heard of Tdap, of which 9.4% reported that a healthcare provider had recommended it. A low perceived risk of contracting pertussis was the single most common reason for either not vaccinating with Tdap or being unwilling to do so (44.7%). Most unvaccinated respondents (81.8%) indicated a willingness to receive Tdap if it was recommended by a provider.

Conclusions

During the first two years of availability, Tdap uptake was likely inhibited by a low collective awareness of Tdap and a low perceived risk of contracting pertussis among U.S. adults, as well as a paucity of provider-to-patient vaccination recommendations. Significant potential exists for improved coverage, as many adults were receptive to vaccination.     

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).     

Universal tetanus,diphtheria, acellular pertussis (Tdap) vaccination of adults: What the Canadian public knows and wants to know

Tetanus, diphtheria, and acellular pertussis vaccine (Tdap) is recommended for all adults in Canada but uptake is low. This study measured the knowledge, attitudes, beliefs, and behaviors of Canadian adults to identify potential barriers and facilitators to Tdap uptake. A survey was undertaken on a geographically representative sample of Canadian adults (n = 4023) and 8 focus groups (62 participants) were conducted nationwide. The survey revealed that knowledge about pertussis and Tdap was low (38.3% correct answers). Only 36.0% of respondents reported being aware that all adults were recommended to receive Tdap and only 10.7% reported being immunized; 36.7% did not know whether they had received Tdap. Respondents who were aware of the immunization recommendations were twice as likely to be immunized (16.6% vs. 8.3%; p < 0.001). Only 9.3% believed that their health care provider thought that Tdap was important for adults. The focus group data supported the survey results. Participants wanted information about pertussis and Tdap communicated through multiple modalities, but a recommendation by their family physician was most important to their decision to be immunized or not. This study demonstrates that current recommendations for universal adult vaccination with Tdap are not reaching the general public in Canada and an alternative strategy will be required to improve Tdap vaccine uptake.     

A randomized Phase III clinical trial to assess the efficacy of a bovine-human reassortant pentavalent rotavirus vaccine in Indian infants

Rotavirus is the most common cause of moderate-to-severe infant diarrhoea in developing countries, resulting in enormous morbidity, mortality, and economic burden. A bovine-human reassortant pentavalent rotavirus vaccine (BRV-PV) targeting the globally most common strains was developed in India and tested in a randomized, double-blind, placebo-controlled end-point driven Phase III efficacy clinical trial implemented at six sites across India. Infants 6 to 8 weeks of age were randomized (1:1) to receive three oral doses of BRV-PV or placebo at 6, 10, and 14 weeks of age along with routine vaccines. Home visit surveillance was conducted to detect severe rotavirus gastroenteritis (SRVGE) and safety outcomes until the children reached two years of age. A total of 3749 infants received BRV-PV while 3751 received placebo. At the time of the primary end-point (when the minimum number of cases needed for analysis were accrued) the vaccine efficacy against SRVGE was 36% (95% CI 11.7, 53.6, p = 0.0067) in the per protocol (PP) analysis, and 41.9% (95% CI 21.1, 57.3, p = 0.0005) in the intent to treat (ITT) analysis. Vaccine efficacy over the entire follow-up period (until children reached two years of age) was 39.5% (95% CI 26.7, 50, p < 0.0001) in the PP analysis and 38.8% (95% CI, 26.4, 49, p < 0.0001) in the ITT analysis. Vaccine efficacy against the very severe rotavirus cases (VSRVGE, Vesikari score ≥ 16) was 60.5% (95% CI 17.7, 81, p = 0.0131) at the time of the primary analysis and 54.7% (95% CI 29.7, 70.8, p = 0.0004) for the complete follow-period in the PP population. The incidence of solicited, unsolicited, and serious adverse events were similar in both the vaccine and placebo groups. Likewise, the number of intussusceptions and deaths were similar between both groups. Thus, BRV-PV is an effective, well tolerated and safe vaccine in Indian infants. (Trial registration: Clinical Trials.Gov [NCT 02133690] and Clinical Trial Registry of India [CTRI/2013/05/003667]).     

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.     

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.     

A phase 3, randomized,active-controlled study to assess the safety and tolerability of meningococcal serogroup B vaccine bivalent rLP2086 in healthy adolescents and young adults

BackgroundNeisseria meningitidis serogroup B (MnB) is an important cause of invasive meningococcal disease (IMD). A MnB vaccine (bivalent rLP2086, Trumenba^®) consisting of 2 factor H binding protein variants received accelerated approval in the United States for the prevention of IMD caused by MnB in individuals 10–25 years of age. This randomized, active-controlled, observer-blind study further assessed the safety and tolerability of bivalent rLP2086.MethodsEligible subjects ≥10 to <26 years were randomized (2:1) to receive bivalent rLP2086 at months 0, 2, and 6, or hepatitis A virus vaccine (HAV, Havrix^®) at months 0 and 6, and saline at month 2. The primary endpoints were serious adverse events (SAEs) throughout the study and medically-attended adverse events (MAEs) within 30 days after vaccination. Additional safety assessments included SAEs at other study intervals and adverse events (AEs) during the vaccination phase.ResultsOf 5712 subjects randomized, 84.6% (n = 3219) of bivalent rLP2086 recipients and 87.2% (n = 1663) of HAV/saline recipients completed the study. Throughout the study, SAEs were reported for 1.6% and 2.5% of bivalent rLP2086 and HAV/saline recipients, respectively. SAEs related to either vaccine were rare. MAEs occurred in 7.0% and 6.1% of subjects after vaccination 1; 5.5% and 6.1% after vaccination 2; and 5.3% and 5.5% after vaccination 3 in the bivalent rLP2086 and HAV/saline groups, respectively. A greater proportion of subjects reported AEs during the vaccination phase after bivalent rLP2086 compared with HAV/saline recipients; however, when reactogenicity events were excluded, the proportion between groups was similar.ConclusionThis safety study, the largest randomized, active-controlled trial evaluating a recombinant MnB vaccine, demonstrated that bivalent rLP2086 is safe and tolerable in healthy individuals ≥10 to <26 years of age.     

A novel peptide-based pan-influenza A vaccine: A double blind,randomised clinical trial of immunogenicity and safety

BackgroundFP-01.1 is a novel synthetic influenza A vaccine consisting of six fluorocarbon-modified 35-mer peptides that encapsulate multiple CD4+ and CD8+ T-cell epitopes and is designed to induce an immune response across a broad population.MethodsFP-01.1 was evaluated for safety and immunogenicity in a randomised, double-blind, placebo-controlled, dose-escalation, phase I clinical study in healthy adult volunteers (n = 49). IFNγ ELISpot assays and multicolour flow cytometry were used to characterise the immune response.ResultsFP-01.1 was safe and well tolerated at all doses tested with a similar adverse event profile in actively vaccinated subjects compared with controls. Maximum immunogenicity was in the 150 μg/peptide dose group where a robust response (243 spots/million PBMC) was demonstrated in 75% subjects compared with 0% in placebo controls. All six peptides were immunogenic. FP-01.1 induced dual CD4+ and CD8+ T cell responses and vaccine-specific T cells cross-recognise divergent influenza strains.ConclusionsThis first-in-human study showed that FP-01.1 has an acceptable safety and tolerability profile and generated robust anti-viral T cell responses in a high proportion of subjects tested. The results support the further clinical testing of FP-01.1 prior to clinical, proof-of-concept, live viral challenge studies.     

Impact and cost-effectiveness of a second tetanus toxoid,reduced diphtheria toxoid,and acellular pertussis (Tdap) vaccine dose to prevent pertussis in the United States

IntroductionThe United States experienced a substantial increase in reported pertussis cases over the last decade. Since 2005, persons 11 years and older have been routinely recommended to receive a single dose of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) vaccine. The objective of this analysis was to evaluate the potential impact and cost-effectiveness of recommending a second dose of Tdap.MethodsA static cohort model was used to calculate the epidemiologic and economic impact of adding a second dose of Tdap at age 16 or 21 years. Projected costs and outcomes were examined from a societal perspective over a 20-year period. Quality-adjusted Life Years (QALY) saved were calculated.ResultsUsing baseline pertussis incidence from the National Notifiable Diseases Surveillance System, Tdap revaccination at either age 16 or 21 years would reduce outpatient visits by 433 (5%) and 285 (4%), and hospitalization cases by 7 (7%) and 5 (5%), respectively. The costs per QALY saved with a second dose of Tdap were approximately US $19.7 million (16 years) and $26.2 million (21 years). In sensitivity analyses, incidence most influenced the model; as incidence increased, the costs per QALY decreased. To a lesser degree, initial vaccine effectiveness and waning of effectiveness also affected cost outcomes. Multivariate sensitivity analyses showed that under a set of optimistic assumptions, the cost per QALY saved would be approximately $163,361 (16 years) and $204,556 (21 years).ConclusionA second dose of Tdap resulted in a slight decrease in the number of cases and other outcomes, and that trend is more apparent when revaccinating at age 16 years than at age 21 years. Both revaccination strategies had high dollar per QALY saved even under optimistic assumptions in a multivariate sensitivity analysis.     

Adverse events after tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) vaccine administered to adults 65 years of age and older reported to the Vaccine Adverse Event Reporting System (VAERS), 2005-2010

Background

Tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine was not licensed for use in adults aged ≥65 years due to lack of sufficient efficacy and safety data.

Objective

To characterize reports to the Vaccine Adverse Event Reporting System (VAERS) among adults aged ≥65 years who received Tdap vaccine ‘off-label’ to assess for potential vaccine safety concerns.

Methods

We searched VAERS for US reports of adverse events (AEs) in subjects aged ≥65 years who received Tdap vaccine from 9/1/2005 to 9/08/2010. Medical records were requested for all reports coded as serious (death, hospitalization, prolonged hospitalization, permanent disability, life-threatening-illness). Proportional reporting ratio (PRR) was used to assess for higher proportionate reporting for AEs after Tdap compared with Td reports in subjects aged ≥65 years.

Results

VAERS received 243 reports following Tdap administered to persons aged ≥65 years. Eleven (4.5%) reports were serious, including two deaths. Most common AEs were local reactions in 100 (41.2%) reports. Seventy-eight (32.1%) reports contained coding terms that denoted inappropriate administration of vaccine. ‘Cough’ was the only term associated with disproportionately higher reporting after Tdap compared with Td. Six of seven Tdap reports containing the term ‘Cough’ were non-serious. Clinical review of serious reports identified no unusual patterns of AEs.

Conclusion

Our VAERS review of the ‘off-label’ use of Tdap vaccine in adults ≥65 years did not find any safety concerns that warrant further study. These data will provide useful baseline information to assist CDC and FDA with monitoring efforts as permissive recommendations for Tdap in older persons are adopted.     

Immunogenicity and safety of a modified three-dose priming and booster schedule for the Hantaan virus vaccine (Hantavax): A multi-center phase III clinical trial in healthy adults

BackgroundHemorrhagic fever with renal syndrome is a serious health problem in Eurasian countries. This study aimed to evaluate the immunogenicity and safety of formalin-inactivated Hantaan virus vaccine (Hantavax®) with a 3 + 1 vaccination schedule.MethodsA phase III, multi-center clinical trial was conducted to evaluate the immunogenicity and safety of Hantavax® (three primary doses and a booster dose schedule at 0, 1, 2 and 13 months) among healthy adults. Immune responses were assessed using the plaque reduction neutralizing antibody test (PRNT) and immunofluorescent antibody assay (IFA). Systemic and local adverse events were assessed.ResultsA total of 320 healthy subjects aged ≥19 years were enrolled. Following three primary doses of Hantavax®, the seroconversion rate was 80.97% and 92.81% by PRNT and IFA, respectively. With booster administration, seropositive rates were 67.47% and 95.68% at one-month post-vaccination according to PRNT and IFA, respectively. Solicited local and systemic adverse events were reported in 30.50–42.81% and 16.67–33.75% during the three primary dose vaccination, while those were reported 36.57% and 21.36% after the booster doses. Both local and systemic adverse events did not increase with repeated vaccinations.ConclusionHantavax® showed a high seroconversion rate after the three-dose priming, and additional dose administration with 11-month interval induced good booster effects. (ClinicalTrials.gov Identifier: NCT02553837).     

Immune responses following one and two doses of the reformulated,bivalent, killed,whole-cell,oral cholera vaccine among adults and children in Kolkata,India: A randomized,placebo-controlled trial

Immune responses after one and two doses of the reformulated killed oral cholera vaccine were measured in a double-blind, randomized, placebo-controlled trial of 77 adults aged 18–40 years and 77 children aged 1–17 years residing in Kolkata, India. 65% of adults and 87% of children and 46% of adults and 82% of children exhibited a ≥4-fold rise in serum Vibrio cholerae O1 vibriocidal antibody titers from baseline following dose 1 and 2, respectively. Responses to V. cholerae O139 were less pronounced but followed a similar pattern. We demonstrate that in a cholera-endemic area, the vaccine elicited vibriocidal responses after a single-dose of the vaccine.     

Economic impact of implementing decennial tetanus toxoid,reduced diphtheria toxoid and acellular pertussis (Tdap) vaccination in adults in the United States

BackgroundIn the United States, persons ≥11 years are recommended to receive one dose of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) vaccine, followed by decennial tetanus- and diphtheria-toxoid (Td) boosters. Many providers use Tdap instead of Td. We evaluated epidemiologic and economic impacts of replacing Td boosters with Tdap.MethodsWe used a static cohort model to examine replacing Td with Tdap over the lifetime of 4,386,854 adults ≥21 years. Because pertussis is underdiagnosed and true incidence is unknown, we varied incidence from 2.5 cases/100,000 person-years to 500 cases/100,000 person-years. We calculated vaccine and medical costs from claims data. We estimated cost per case prevented and per quality-adjusted life year (QALY) saved; sensitivity analyses were conducted on vaccine effectiveness (VE), protection duration, vaccine cost, disease duration, hospitalization rates, productivity loss and missed work. We did not include programmatic advantages resulting from use of a single tetanus-toxoid containing vaccine.ResultsAt lowest incidence estimates, administering Tdap resulted in high costs per averted case ($111,540) and QALY saved ($8,972,848). As incidence increased, cases averted increased and cost per QALY saved decreased rapidly. With incidence estimates of 250 cases/100,000 person-years, cost per averted case and QALY saved were $984 and $81,678 respectively; at 500 cases/100,000 person-years, these values were $427 and $35,474. In multivariate sensitivity analyses, assuming 250 cases/100,000 person-years, estimated cost per QALY saved ranged from $971 (most favorable) to $217,370 (least favorable).ConclusionsOur findings suggest that replacing Td with Tdap for the decennial booster would result in high cost per QALY saved based on reported cases. However, programmatic considerations were not accounted for, and if pertussis incidence, which is incompletely measured, is assumed to be higher than reported through national surveillance, substituting Tdap for Td may lead to moderate decreases in pertussis cases and cost per QALY.     

A Phase III open-label,randomized, active controlled clinical study to assess safety,immunogenicity and lot-to-lot consistency of a bovine-human reassortant pentavalent rotavirus vaccine in Indian infants

BackgroundA heat-stable bovine-human rotavirus reassortant pentavalent vaccine (BRV-PV, ROTASIIL®) was developed in India. In this study, the vaccine was tested for safety, immunogenicity and clinical lot-to-lot consistency.MethodsThis was a Phase III, open label, randomized, equivalence design study. The primary objective was to demonstrate lot-to-lot consistency of BRV-PV. Subjects were randomized into four arms, three arms received Lots A, B, and C of BRV-PV and the control arm, received Rotarix®. Three doses of BRV-PV or two doses of Rotarix® and one dose of placebo were given at 6, 10, and 14 weeks of age. Blood samples were collected four weeks after the third dose to assess rotavirus IgA antibody levels. The three lots of BRV-PV were equivalent if the 95% Confidence Intervals (CIs) of the geometric mean concentration (GMC) ratios were between 0.5 and 2. Solicited reactions were collected by using diary cards.ResultsThe study was conducted in 1500 randomized infants, of which 1341 infants completed the study. The IgA GMC ratios among the three lots were around 1 (Lot A versus Lot B: 1.07; Lot A versus Lot C: 1.06; and Lot B versus Lot C: 0.99). The 95% CIs for the GMC ratios were between 0.78 and 1.36. The IgA GMCs were: BRV-PV group 19.16 (95% CI 17.37–21.14) and Rotarix® group 10.92 (95% CI 9.36–12.74) (GMC ratio 1.75; 90% CI 1.51–2.04). Seropositivity rates were 46.98% (95% CI 43.86–50.11) and 31.12% (95% CI 26.17–36.41). The incidence of solicited reactions was comparable across the four arms. No serious adverse events were associated with the study vaccines, except two gastroenteritis events in the BRV-PV groups.ConclusionLot-to-lot consistency of BRV-PV was demonstrated in terms of GMC ratios of IgA antibodies. The vaccine safety and immunogenicity profiles were similar to those of Rotarix®.Clinical Trials.Gov [NCT02584816] and Clinical Trial Registry of India [CTRI/2015/07/006034].     

A randomized,double-blind,non-inferiority trial comparing the immunogenicity and safety of two seasonal inactivated influenza vaccines in adults

BackgroundTo enhance the production and availability of influenza vaccines in different regions of the world is paramount to mitigate the global burden of this disease. Instituto Butantan developed and manufactured an embryonated egg-based inactivated split-virion trivalent seasonal influenza vaccine as part of a technology transfer partnership with Sanofi Pasteur.MethodsThis is a phase IV, randomized, double-blind, active-controlled, multicenter clinical trial including adults 18–60 and > 60 years recruited during the 2019 southern hemisphere influenza season. Subjects were randomized 1:1 to receive either the Sanofi Pasteur Trivalent Seasonal Influenza Vaccine (SP-TIV) or Instituto Butantan Trivalent Seasonal Influenza Vaccine (IB-TIV). Hemagglutinin inhibition antibody titers were assessed pre-vaccination and 21 days post-vaccination.Results624 participants were randomized and vaccinated. In both intention-to-treat and per-protocol analysis, non-inferiority of the SP-TIV versus IB-TIV was demonstrated for the three influenza strains. In the per-protocol analysis, the SP-GMT/IB-GMT ratios for H1N1, H3N2, and B were 0.9 (95%CI, 0.7–1.1), 1.2 (95%CI, 1.0–1.4), and 1.1 (95%CI, 0.9–1.3), respectively. Across vaccination groups, the most common adverse reactions (AR) were limited to the injection-site, including pain and tenderness. The majority of the ARs were graded 1 and/or 2 and lasted less than one day. No serious adverse reaction was observed.ConclusionThis study demonstrated the non-inferiority of the immunogenicity of a single-dose of Instituto Butantan versus a single dose of the Sanofi Pasteur Seasonal Trivalent Influenza Vaccine in adults. Both vaccines were well tolerated and presented similar safety profiles.     

An open label Phase I trial of a live attenuated H6N1 influenza virus vaccine in healthy adults

Background

We describe the results of an open label Phase I trial of a live attenuated H6N1 influenza virus vaccine (ClinicalTrials.gov Identifier: NCT00734175).

Methods and findings

We evaluated the safety, infectivity, and immunogenicity of two doses of 10⁷ TCID₅₀ of the H6N1 Teal HK 97/AA ca vaccine, a cold-adapted and temperature sensitive live, attenuated influenza vaccine (LAIV) in healthy seronegative adults.Twenty-two participants received the first dose of the vaccine, and 18 received the second dose of vaccine 4 weeks later. The vaccine had a safety profile similar to that of other investigational LAIVs bearing avian hemagglutinin (HA) and neuraminidase (NA) genes. The vaccine was highly restricted in replication: two participants had virus detectable by rRT-PCR beyond day 1 after each dose. Antibody responses to the vaccine were also restricted: 43% of participants developed a serum antibody response as measured by any assay: 5% by hemagglutination-inhibition assay, 5% by microneutralization assay, 29% by ELISA for H6 HA-specific IgG and 24% by ELISA for H6 HA specific IgA after either 1 or 2 doses. Following the second dose, vaccine specific IgG and IgA secreting cells as measured by ELISPOT increased from a mean of 0.6 to 9.2/10⁶ PBMCs and from 0.2 to 2.2/10⁶ PBMCs, respectively.

Conclusion

The H6N1 LAIV had a safety profile similar to that of LAIV bearing other HA and NA genes, but was highly restricted in replication in healthy seronegative adults. The H6N1 LAIV was also not as immunogenic as the seasonal LAIV.     

A Phase 1, double-blind,randomized, placebo-controlled study to evaluate the safety and immunogenicity of a tetravalent live attenuated dengue vaccine in adults

BackgroundDengue fever is an important public health problem, especially in Asia and South America. A tetravalent live attenuated dengue vaccine was manufactured in India after receipt of vaccine strains from NIAID, NIH, USA.MethodsThis was a Phase 1, double-blind, randomized, placebo-controlled study performed in 60 healthy adults of 18 to 45 years. Participants were randomized 2:1 to receive a single subcutaneous injection of either a tetravalent live attenuated dengue vaccine or placebo. Safety was assessed by unsolicited adverse events (AEs) and solicited reactions through 21 days after vaccination and serious adverse events (SAEs) through the entire study period of 180 days. Dengue viremia was assessed at baseline and on day 9, 11 and 13 post-vaccination using a plaque assay. Immunogenicity was assessed using the plaque reduction neutralization test (PRNT) assay using vaccine-matched wild virus serotypes (DENV 1, DENV 2, DENV 3 and DENV 4) at baseline and on 56-, 84- and 180-days post-vaccination. PRNT assay using circulating wild type DENV 1, DENV 2, DENV 3 and DENV 4 were done on day 1 and day 85 for a subset of 31 participants.Results60 participants were randomized to receive dengue vaccine (n = 40) or placebo (n = 20). 23 participants (59 %) showed DENV vaccine viremia post- vaccination for any of the four serotypes with majority on day 9 and day 11. At baseline, all participants were naïve by dengue PRNT₅₀ for all four serotypes in both the study groups except for four in the dengue vaccine group and two in the placebo group. On day 57, the GMTs of neutralizing antibodies ranged from 66.76 (95 % CI 36.63, 121.69) to 293.84 (95 % CI 192.25, 449.11) for all four serotypes in the dengue vaccine group. On day 181 though the titers declined, they still remained much higher than the baseline. The titers in the placebo group did not change after vaccination. Seroconversion through day 85 ranged from 79.5 % for DENV 1 to 100 % for DENV2 while in the placebo group, no participant showed seroconversion through day 85. Similar trends were noted when PRNT was done using wild DENV serotypes in both vaccine and placebo groups.Among solicited reactions, injection site erythema, rash, headache, fatigue, myalgia and arthralgia were reported more frequently in the vaccine group than placebo group. All solicited reactions were of grade 1 or grade 2 severity and completely resolved. One unrelated serious adverse event was reported in the vaccine group.ConclusionA single dose of dengue vaccine was safe and well tolerated in adults. The vaccine was highly immunogenic with trivalent or tetravalent seroconversion and seropositivity in most of the participants.The study was funded by Serum Institute of India Pvt. Ltd., Pune, India. ClinicalTrials.gov: NCT04035278.     

Phase I clinical trial of O-acetylated pectin conjugate,a plant polysaccharide based typhoid vaccine

Background

Typhoid fever remains an important cause of morbidity and mortality in the developing countries. Vi capsular polysaccharide conjugate vaccine demonstrated safety and efficacy in young children in high endemic regions. A novel typhoid conjugate vaccine based on plant polysaccharide pectin was studied in a phase I trial.

Methods

Fruit pectin, having the same carbohydrate backbone structure as Vi, was purified from citrus peel and used as the polysaccharide source to prepare a semi-synthetic typhoid conjugate vaccine. Pectin was chemically O-acetylated (OAcPec) to antigenically resemble Vi and conjugated to carrier protein rEPA, a recombinant exoprotein A from Pseudomonas aeruginosa. 25 healthy volunteers, 18–45 years old, were injected once with OAcPec-rEPA. Safety and IgG antibodies reactive with Vi and pectin were analyzed.

Results

No vaccine associated serious adverse reaction was reported. Six weeks after the injection of OAcPec-rEPA, 64% of the volunteers elicited >4-fold rise of anti-Vi IgG. At 26 weeks the level declined, but the difference between the levels at 6 and 26 weeks are not statistically significant. There is a direct correlation between the level of anti-Vi IgG before and after the injection (R² = 0.96). The anti-Vi IgG can be absorbed by Vi, but not by pectin. There was no corresponding increase of anti-pectin after the injection, indicating the antibody response to OAcPec-rEPA was specific to Vi. There is no Vi-rEPA data in US adults for comparison of immune responses. The OAcPec-rEPA elicited significantly less IgG anti-Vi in US adults than those by Vi-rEPA in Vietnamese adults.

Conclusion

The O-acetylated pectin conjugate, a plant based typhoid vaccine, is safe and immunogenic in adult volunteers.ClinicalTrial.gov identifier: NCT00277147, NIH Protocol ID number: OH06-CH-0070, FDA BB Investigation New Drug (IND) number 6989.     

Immunogenicity and safety of a fully liquid aluminum phosphate adjuvanted Haemophilus influenzae type b PRP-CRM197-conjugate vaccine in healthy Japanese children: A phase III,randomized, observer-blind,multicenter, parallel-group study

BackgroundBroad use of monovalent Haemophilus influenzae type b (Hib) conjugate vaccines based on the capsular polysaccharide polyribosyl-ribitol phosphate (PRP), has significantly reduced invasive Hib disease burden in children worldwide, particularly in children aged <1 year. In Japan, PRP conjugated to tetanus toxoid (PRP-T) vaccine has been widely used since the initiation of public funding programs followed by a routine vaccination designation in 2013.MethodsWe compared the immunogenicity and safety of PRP conjugated to a non-toxic diphtheria toxin mutant (PRP-CRM₁₉₇) vaccine with the PRP-T vaccine when administered subcutaneously to healthy Japanese children in a phase III study. Additionally, we evaluated the immunogenicity and safety profiles of a diphtheria–tetanus acellular pertussis (DTaP) combination vaccine when concomitantly administered with either PRP-CRM₁₉₇ or PRP-T vaccines. The primary endpoint was the “long-term seroprotection rate”, defined as the group proportion with anti-PRP antibody titers ⩾1.0 μg/mL, after the primary series.ResultsLong-term seroprotection rates were 99.3% in the PRP-CRM₁₉₇ group and 95.6% in the PRP-T group. The intergroup difference (PRP-CRM₁₉₇ group – PRP-T group) was 3.7% (95% confidence interval: 0.099–7.336), demonstrating that PRP-CRM₁₉₇ vaccine was non-inferior to PRP-T vaccine (p < 0.0001). Furthermore, the “short-term seroprotection rate” (anti-PRP antibody titer ⩾0.15 μg/mL) before booster vaccination was higher in the PRP-CRM₁₉₇ group than in PRP-T. Concomitant administration of PRP-CRM₁₉₇ vaccine with DTaP vaccine showed no differences in terms of immunogenicity compared with concomitant vaccination with PRP-T vaccine and DTaP vaccine. Although CRM₁₉₇ vaccine had higher local reactogenicity, overall, both Hib vaccines had acceptable safety and tolerability profiles.ConclusionThe immunogenicity of PRP-CRM₁₉₇ vaccine administered subcutaneously as a three-dose primary series in children followed by a booster vaccination 1 year after the primary series induced protective levels of Hib antibodies with no safety or tolerability concerns.Clinical trial registry: Registered on ClinicalTrials.gov: NCT01379846     

A phase 1 randomized open-label clinical study to evaluate the safety and tolerability of a novel recombinant hepatitis E vaccine

BackgroundThis study aimed to evaluate the safety and tolerability for variable dosages of a novel hepatitis E vaccine p179.MethodsThe randomized open-label parallel control phase 1 clinical trial enrolled 120 eligible participants aged 16–65 years in Jiangsu Province, China. The experimental groups were randomized to receive different dosages of 20 μg, 30 μg, and 40 μg Hepatitis E Virus (HEV) p179 vaccines, with the 30 μg HEV vaccine p239 Hecolin as control, and vaccinated at 0, 1 and 6 month intervals. Participants were observed for solicited local and systemic adverse reactions (ARs) occurring within 7 days after each vaccination, and any serious adverse events (SAEs) occurring within 6 months post-vaccination. Blood samples were collected from participants 3 days before and after each injection, to determine the blood routine and serum biochemical indexes.ResultsThe solicited local ARs incidence in experimental groups were significantly lower than that of the control group (P = 0.027). The difference between solicited total and systemic ARs incidence of experimental groups and the control group were not significant (P > 0.05). Similar patterns were observed when the analyses were performed on the group having ARs of varying grades and symptoms. All changes in blood biochemical indexes and routine blood tests before and after different vaccinations were mild (grade 1) or moderate (grade 2), and the difference in experimental groups and the control group were not statistically significant. No vaccine related SAEs occurred in any of the subjects during the study.ConclusionThree different dosages of HEV p179 vaccine were deemed safe and well tolerated. No vaccine-associated SAEs were identified, and the 30 μg dosage formulation was selected for further investigation for efficacy.Clinical trials registration number: 2012L01657.