Fever following administration of two inactivated influenza vaccines--a survey of parents of New Zealand infants and children 5 years of age and under

Due to a dramatic increase in reported febrile convulsions in Western Australia following a routine pediatric influenza vaccination programme we evaluated parental recall of fever in their child following 2010 trivalent influenza vaccine manufactured by either Sanofi Pasteur (Vaxigrip^®) or CSL Biotherapies (Fluvax^®) to determine if the rates of febrile events in infants and children 5 years and under following administration of either Vaxigrip^® or Fluvax^® were significantly different.

Method

A convenience sample of New Zealand General practices who had received stocks of the vaccines of interest consecutively contacted parents of infants and children under 5 years of age who received at least one dose of 2010 influenza vaccine. A brief questionnaire was administered with the main outcome parental recall of fever within 24 h of vaccination.

Results

Response rate was 99%. There were 327 parents of children aged 6 months to 5 years attending one of 23 primary care practices who had received a dose of either the Vaxigrip^® or Fluvax^® vaccine between 4th March and 28th June 2010 surveyed. A total of 422 doses were given of which 267 were Vaxigrip^®, 133 were Fluvax^® and 22 another vaccine. Fever occurred significantly more frequently within 24 h following administration of Fluvax^® compared with Vaxigrip^® RR 4.33 (2.44-7.70). When fevers were measured they were, on average, higher in the Fluvax^® vaccines (38 °C compared with 39 °C). Additionally, recipients were more likely to seek medical advice for fever following Fluvax^® RR 23.11 (2.96-180.12).

Conclusions

There is considerable variation in reactogenicity between two 2010 seasonal vaccines in infants and young children. Vaxigrip^® is significantly less reactogenic when compared to Fluvax^® in this population in which Fluvax^® is associated with unacceptably high rates of febrile reactions. There has been insufficient safety evaluation of seasonal influenza vaccine safety in this population.     

General practice encounters following seasonal influenza vaccination as a proxy measure of early-onset adverse events

Background

In 2010, use of seasonal trivalent influenza vaccine (TIV) in children <5 years of age was suspended in Australia following reports of vaccine-related febrile convulsions. We investigated the utility of data on primary care [general practice (GP)] consultations for any reason within three days of receipt of influenza vaccine as recorded on the Australian Childhood Immunisation Register (ACIR) as a means of signal detection.

Methods

Data on GP consultations were obtained from Medicare Australia (Australian Government Department of Human Services) for children recorded on the ACIR as receiving either TIV or monovalent influenza vaccine. Rates of GP consultation by day following ACIR-recorded receipt of influenza vaccine were compared by year (2008–2010), vaccine type, age and region.

Results

In 2010, GP encounter rates on the day after receipt of the TIV manufactured by bioCSL (formerly CSL Biotherapies (Fluvax^®) were significantly higher than both bioCSL TIVs in the previous two years [rate ratio (RR) 1.9; 95% CI: 1.7–2.2] and Sanofi Pasteur TIV, Vaxigrip^® [RR 1.6, 95% CI 1.4–1.7] in 2009–2010. Encounter rates were also higher than for CSL Monovalent influenza vaccine, Panvax^® [RR 1.9, 95% CI 1.7–2.2] in 2009–2010. These findings were robust to adjustment for age group (≤2, >2 years) and region (Western Australia vs other Australian states/territories).

Conclusions

A primary care consultation on the day after vaccine receipt is a reasonable proxy for early reactogenicity and has potential for use in various settings.     

Trivalent influenza vaccine and febrile adverse events in Australia, 2010: clinical features and potential mechanisms

Introduction

Increased numbers of children presenting with febrile adverse events following trivalent influenza vaccine (TIV) were noted in Australia in 2010. We describe the epidemiology and clinical features of the adverse events and explore the biological basis for the adverse events using an in vitro model.

Materials and Methods

Children presenting to a tertiary paediatric hospital in 2010 with adverse events within 72 h of TIV were retrospectively reviewed. Demographics, clinical features, physiological variables and outcomes were examined. Plasma cytokine and chemokine levels were examined in a subgroup of children with vaccine-related febrile convulsions. Peripheral blood mononuclear cells of age-matched children were stimulated with different TIV preparations. Inflammatory cytokine and chemokine analysis was performed on cultured supernatants.

Results

Vaccine-related febrile adverse events were identified in 190 children. Most occurred in healthy children (median age: 1.5 years) within 12 h of vaccination. Twenty-eight (14.7%) required hospital admission. High temperature ≥39.0 °C (101/190; 53%), vomiting (120/190; 63%) and convulsions (38/190; 20%) were common. All children presenting had received Fluvax^® or Fluvax Junior^®.In the in vitro model, IFN-α, IL-1β, IL-6, IL-10, IP-10 and MIP-1α levels were significantly higher when measured at 6 and 24 h in cultures stimulated with Fluvax^® compared with alternative 2010 TIV preparations.

Conclusions

Numerous febrile adverse events (including febrile seizures) were observed following Fluvax^® or Fluvax Junior^® in 2010. Clear differences in cytokine production were observed when peripheral blood mononuclear cells were stimulated with Fluvax^® compared with alternate TIV preparations. Increased awareness of these potential adverse events is required to ensure earlier detection and prevention in the future.     

Vaccination with 3-dose paediatric rotavirus vaccine (RotaTeq®): impact on the timeliness of uptake of the primary course of DTPa vaccine

Background

In countries like Australia where high coverage rates of early childhood vaccines has been achieved, ensuring timely vaccination is the next challenge – particularly where multiple doses are required for protection (e.g. DTPa vaccine). Since July 2007, for the first time, the Australian childhood vaccination schedule has included a vaccine (rotavirus vaccine) that must be administered within strict dosing windows.

Aim

To determine whether the introduction of a 3-dose rotavirus vaccine (RotaTeq^®) into the national childhood immunisation program in Victoria, Australia, had an impact on the timeliness of the primary course of DTPa vaccine that is also scheduled at the same ages (2, 4 and 6 months).

Study

We studied de-identified data of >17,000 children residing in four large and culturally diverse localities in the Eastern Region of Melbourne, Victoria who were born prior to or after the introduction of RotaTeq^® into the National Immunisation Program schedule. Timeliness was defined as the proportion of children who received a particular dose of DTPa vaccine within the dosing window for the equivalent dose of RotaTeq^®. We were particularly interested in any change in the timeliness of dose 3 of DTPa vaccine.

Results

Before the introduction of RotaTeq^®, timely uptake of doses 1 and 2 of DTPa vaccine was high (93–97%). However, timeliness of the 3rd dose was markedly lower, dropping to 80% in one locality. In the post-RotaTeq^® cohort, rates of timely uptake for doses 1 and 2 of DTPa vaccine remained high (97–99%). However, for DTPa vaccine dose 3, there was a clear trend toward improved timeliness – increasing by 5 to up to 12 percentage points compared with the pre-RotaTeq^® cohort.

Conclusion

Inclusion in the national immunisation schedule of the 3-dose vaccine RotaTeq^® that has strict dosing windows encourages parents to present in a timely fashion for their child's vaccination, which in turn may drive an improvement in timeliness of other concurrently scheduled vaccines (e.g. DTPa). Introduction of government-funded RotaTeq^® may improve the uptake of the crucial 3rd dose of DTPa vaccine, where traditionally the greatest delays are noted.     

AdimFlu-S(®) influenza A (H1N1) vaccine during pregnancy: the Taiwanese Pharmacovigilance Survey

Background

This study evaluated the incidence, nature, and seriousness of adverse drug reactions (ADRs) occurring after AdimFlu-S^® influenza A (H1N1) vaccination in pregnant women was administered.

Methods

This is a retrospective cohort study. Between October 2009 and February 2010, 198 pregnant women who had received the AdimFlu-S^® influenza A (H1N1) vaccine during pregnancy and 198 age-matched pregnant women who had not received influenza vaccine were included and recorded. The pregnancy outcome and maternal adverse effects were extracted from chart reviews. Infant health status data were followed up until 8 weeks post-partum.

Results

During the observation period of each cohort, four subjects (2.0%) in the exposed group experienced vaccine-related adverse events that were mild in severity. A total of 17 women (8.6%) in the vaccine exposed group and 40 women (20.2%) in the unexposed group underwent at least one adverse effect during their pregnancy. A total of 72 infants (35.6%) in the exposed group and 101 infants (49%) in the unexposed group had at least one adverse event within 8 weeks after they were born (p < 0.05). The adverse events experienced by the women and their infants were not increased when the vaccine was administered during the first trimester. There were no significant differences between these two groups with regard to preterm delivery rate and stillbirth rate.

Conclusion

AdimFlu-S ^® influenza A (H1N1) vaccine is safe for pregnant women and their infants.     

Antibody persistence in mothers one year after pneumococcal immunization in pregnancy

Background

Pneumococcal infections are a significant cause of morbidity and mortality, and young infants are particularly vulnerable to infection. Maternal immunization can protect infants, but there are limited data on the duration of pneumococcal vaccine antibody in pregnant women. We report on maternal antibody concentrations one year after immunization with 23-valent pneumococcal polysaccharide (23vPPS) vaccine.

Method

The Mother's Gift study randomly assigned 340 pregnant Bangladeshi mothers between ages 18 and 36 to receive either inactivated influenza vaccine (Fluarix^®) or the 23vPPS vaccine (Pneumovax^®) during the third trimester. Sera were collected before immunization, at delivery, and at one year post-delivery. We determined anti-capsular IgG antibody to 9 pneumococcal serotypes by a multiplex Luminex ELISA. We report antibody geometric mean concentrations (GMCs) for 9 serotypes, 12 month/delivery geometric mean ratios (GMRs) and proportions seroprotected (>0.35 mcg/mL) in 23vPPS vaccine recipients and controls at delivery and at 12 months.

Results

Among pneumococcal vaccinees, GMCs remained stable, with an overall 12 month/delivery GMR of 0.83 (95% CI, 0.75–0.92). In the control group, GMCs increased with a mean ratio of 1.98 (95% CI, 1.81–2.17; P < 0.0001). GMCs in these vaccinees did not decline significantly in the 12 months after antenatal immunization.

Conclusion

GMCs in these adult vaccinees and controls did not decline significantly in the 12 months after antenatal immunization. Interestingly, mothers who did not receive 23vPPS in pregnancy show a substantial increase of GMC for most serotypes in the first year after immunization. Further studies are needed to determine the need for repeat doses of 23vPPS vaccine in subsequent pregnancies more than a year later.     

Effect of vaccine dose on the safety and immunogenicity of a candidate TB vaccine, MVA85A, in BCG vaccinated UK adults

Purpose

A non-randomised, open-label, Phase I safety and immunogenicity dose-finding study to assess the safety and immunogenicity of the candidate TB vaccine Modified Vaccinia virus Ankara expressing Antigen 85A (MVA85A) from Mycobacterium tuberculosis (MTB) in healthy adult volunteers previously vaccinated with BCG.

Methods

Healthy BCG-vaccinated volunteers were vaccinated with either 1 × 10⁷ or 1 × 10⁸ PFU of MVA85A. All adverse events were documented and antigen specific T cell responses were measured using an ex vivo IFN-γ ELISPOT assay. Safety and immunogenicity were compared between the 2 dose groups and with a previous trial in which a dose of 5 × 10⁷ PFU MVA85A had been administered.

Results

There were no serious adverse events recorded following administration of either 1 × 10⁷ or 1 × 10⁸ PFU of MVA85A. Systemic adverse events were more frequently reported following administration of 1 × 10⁸ PFU of MVA85A when compared to either 5 × 10⁷ or 1 × 10⁷ PFU of MVA85A but were mild or moderate in severity and resolved completely within 7 days of immunisation. Antigen specific T cell responses as measured by the IFN-γ ELISPOT were significantly higher following immunisation in adults receiving 1 × 10⁸ PFU compared to the 5 × 10⁷ and 1 × 10⁷ doses. Additionally, a broader range of Ag85A epitopes are detected following 1 × 10⁸ PFU of MVA85A.

Conclusion

A higher dose of 1 × 10⁸ PFU of MVA85A is well-tolerated, increases the frequency of IFN-γ secreting T cells detected following immunisation and broadens the range of Ag85A epitopes detected.     

Indicators of therapeutic effect in FIT-06, a Phase II trial of a DNA vaccine, GTU(®)-Multi-HIVB, in untreated HIV-1 infected subjects

Background

Combination highly active antiretroviral therapy (HAART) has significantly decreased HIV-1 related morbidity and mortality globally transforming HIV into a controllable condition. HAART has a number of limitations though, including limited access in resource constrained countries, which have driven the search for simpler, affordable HIV-1 treatment modalities. Therapeutic HIV-1 vaccines aim to provide immunological support to slow disease progression and decrease transmission. We evaluated the safety, immunogenicity and clinical effect of a novel recombinant plasmid DNA therapeutic HIV-1 vaccine, GTU^®-multi-HIVB, containing 6 different genes derived from an HIV-1 subtype B isolate.

Methods

63 untreated, healthy, HIV-1 infected, adults between 18 and 40 years were enrolled in a single-blinded, placebo-controlled Phase II trial in South Africa. Subjects were HIV-1 subtype C infected, had never received antiretrovirals, with CD4 ≥ 350 cells/mm³ and pHIV-RNA ≥ 50 copies/mL at screening. Subjects were allocated to vaccine or placebo groups in a 2:1 ratio either administered intradermally (ID) (0.5 mg/dose) or intramuscularly (IM) (1 mg/dose) at 0, 4 and 12 weeks boosted at 76 and 80 weeks with 1 mg/dose (ID) and 2 mg/dose (IM), respectively. Safety was assessed by adverse event monitoring and immunogenicity by HIV-1-specific CD4+ and CD8+ T-cells using intracellular cytokine staining (ICS), pHIV-RNA and CD4 counts.

Results

Vaccine was safe and well tolerated with no vaccine related serious adverse events. Significant declines in log pHIV-RNA (p = 0.012) and increases in CD4+ T cell counts (p = 0.066) were observed in the vaccine group compared to placebo, more pronounced after IM administration and in some HLA haplotypes (B*5703) maintained for 17 months after the final immunisation.

Conclusions

The GTU^®-multi-HIVB plasmid recombinant DNA therapeutic HIV-1 vaccine is safe, well tolerated and favourably affects pHIV-RNA and CD4 counts in untreated HIV-1infected individuals after IM administration in subjects with HLA B*57, B*8101 and B*5801haplotypes.     

A qualitative study of HPV vaccine acceptability among health workers, teachers, parents, female pupils, and religious leaders in northwest Tanzania

Background

As human papillomavirus (HPV) vaccines become available in developing countries, acceptability studies can help to better understand potential barriers and facilitators of HPV vaccination and guide immunisation programs.

Methods

Prior to a cluster-randomised phase IV trial of HPV vaccination delivery strategies in Mwanza Region, Tanzania, qualitative research was conducted to assess attitudes and knowledge about cervical cancer and HPV, and acceptability of and potential barriers to HPV vaccination of Tanzanian primary schoolgirls. Semi-structured interviews (n = 31) and group discussions (n = 12) were conducted with a total of 169 respondents (parents, female pupils, teachers, health workers and religious leaders).

Results

While participants had heard of cancer in general, most respondents had no knowledge of cervical cancer, HPV, or HPV vaccines. Only health workers had heard of cervical cancer but very few knew its cause or had any awareness about HPV vaccines. After participants were provided with information about cervical cancer and HPV vaccination, the majority stated that they would support HPV vaccination of their daughter to protect them against cervical cancer. Opt-out consent for vaccination was considered acceptable. Most preferred age-based vaccination, saying this would target more girls before sexual debut than class-based vaccination. Potential side effects and infertility concerns were raised by 5/14 of participating male teachers.

Discussion

Reported acceptability of HPV vaccination amongst parents, teachers and other community members was high in this population. Respondents stressed the need to provide adequate information about the vaccine to parents, that also addresses side effects and infertility concerns.     

A randomised, single-blind, dose-range study to assess the immunogenicity and safety of a cell-culture-derived A/H1N1 influenza vaccine in adult and elderly populations

Background

Modern cell-culture production techniques and the use of adjuvants helps to ensure that the global demand for pandemic influenza vaccine can be met. This study aimed to assess the immunogenicty and safety profiles of various cell-culture-derived A/H1N1 pandemic vaccine formulations in healthy adult and elderly subjects.

Methods

Adult (18–60 years) subjects (n = 544) received vaccine either containing 3.75 μg of antigen with half the standard dose of MF59^® (Novartis Vaccines and Diagnostics) adjuvant, 7.5 μg antigen with a full dose of MF59, or a non-adjuvanted vaccine containing 15 μg of antigen. Elderly (≥61 years) subjects (n = 268) received either the 3.75 μg or 7.5 μg adjuvanted formulations. Two priming vaccine doses were administered 3 weeks apart, followed by a single booster dose of seasonal influenza vaccine 1 year later. Immunogenicity was assessed 3 weeks after each vaccination. The safety profile of each formulation was evaluated throughout the study.

Results

A single primary dose of each A/H1N1 vaccine formulation was sufficient to meet all three European (CHMP) licensure criteria for pandemic influenza vaccines in adult subjects. Two licensure criteria were met after one vaccine dose in elderly subjects; two primary doses were required to meet all three criteria in this age group. The highest antibody titres were observed in response to the 7.5 μg vaccine containing a full dose of MF59 adjuvant. All subjects rapidly generated seroprotective antibody titres in response to booster vaccination.

Conclusion

This study identified one 3.75 μg vaccine dose containing half the standard dose of MF59 adjuvant as optimal for adults, two doses were optimal for elderly subjects. The antigen-sparing properties of MF59, and rapid, modern, cell-culture production techniques represent significant steps towards meeting the global demand for influenza vaccine.     

A randomized clinical trial to identify the optimal antigen and MF59(®) adjuvant dose of a monovalent A/H1N1 pandemic influenza vaccine in healthy adult and elderly subjects

Background

Vaccines against pandemic A/H1N1 influenza are required to protect the entire population. This dose range study aimed to identify priming antigen and adjuvant doses resulting in optimal levels of antibody-mediated protection after primary and one-year booster immunizations.

Methods

This randomised trial enrolled 410 healthy adult (18–60 years) and 251 healthy elderly (>60 years) participants. Subjects received vaccine containing either 3.75 μg or 7.5 μg antigen, adjuvanted with half the standard dose, or a standard dose of MF59^® (Novartis Vaccines) adjuvant, respectively. An additional adult cohort received non-adjuvanted vaccine containing 15 μg antigen. Two doses of investigational vaccine were administered three weeks apart, followed by a single booster dose of adjuvanted seasonal influenza vaccine one year after priming. Immunogenicity was assessed by haemagglutination inhibition and microneutralization assays pre- and post-immunization, the safety profile of each vaccine was also evaluated.

Results

All of the vaccine formulations investigated were highly immunogenic and well tolerated in both adult and elderly subjects. The 7.5 μg formulation induced the highest antibody titres after primary and booster immunizations, and resulted in better long-term antibody persistence, in both age groups. Assessment according to European licensure criteria for influenza vaccines concluded that single adjuvanted priming doses containing 3.75 μg and 7.5 μg antigen were optimal for the adult and elderly populations, respectively.

Conclusions

These data demonstrate that one priming dose of MF59-adjuvanted A/H1N1 vaccine provided healthy adult (3.75 μg or 7.5 μg formulations) and healthy elderly (7.5 μg formulation) individuals with adequate levels of seroprotection. Booster administration after two priming doses of either vaccine formulation resulted in the rapid development of seroprotective antibody titres.

Trial registration

www.clinicaltrials.gov (NCT00971906).     

Broad HIV-1 neutralizing antibody response induced by heterologous gp140/gp145 DNA prime-vaccinia boost immunization

Objective

To develop an effective HIV vaccine strategy that can induce cross-reactive neutralizing antibody.

Methods

Codon-optimized gp140 and gp145 env genes derived from HIV-1_cn54, a CRF07 B′/C recombinant strain, were constructed as DNA and recombinant Tiantan vaccinia (rTV) vaccines. The effect of heterologous immunization with gp140 and gp145 was tested in mice and guinea pigs. T cell responses were detected using the IFN-γ ELISPOT assay. A panel of primary isolates of clade B′ and B′/C HIV-1 and TZM-bl cells was used to determine the neutralizing activity of immunized sera.

Results

The neutralizing antibodies (NAbs) induced by the heterologous immunogen immunization neutralized all HIV-1 B′ and B′/C primary isolates in the guinea pig model. Gp145 and gp140 heterologous prime-boost induced the best neutralizing antibody response with a broad neutralizing spectrum and the highest titer of 1:270 at 6 weeks after the last inoculation. However, the T cell response to HIV-1 peptides was significantly weaker than the gp145 + gp145 homologous prime-boost.

Conclusions

This heterologous prime-boost immunization strategy could be used to design immunogen-generating broad neutralizing antibodies against genetic variance pathogens.     

Safety and immunogenicity of an MF59(®)-adjuvanted A/H5N1 pre-pandemic influenza vaccine in adults and the elderly

Background

The potential consequences of an avian influenza pandemic warrants the development of safe, highly immunogenic pre-pandemic A/H5N1 vaccines with cross-clade protection. In this randomized, controlled study we compared the immunogenicity and safety of an MF59^®-adjuvanted (Novartis Vaccines, Marburg, Germany) A/H5N1 pre-pandemic vaccine with that of a licensed, MF59-adjuvanted, seasonal influenza vaccine.

Methods

Healthy adult (18–60 years, n = 3372) and elderly (≥61 years, n = 275) volunteers received either an initial dose of a licensed, non-adjuvanted, trivalent, seasonal influenza vaccine (Agrippal^®) on Day 1, followed by one dose of MF59-H5N1 study vaccine on Day 22 and a second dose of MF59-H5N1 on Day 43, or alternatively, placebo on Day 1 followed by one dose of MF59-adjuvanted seasonal reference vaccine on Day 22 and a second dose of reference vaccine on Day 43. Homologous and cross-reactive A/H5N1 antibody responses were analysed by haemagglutination inhibition (HI), single radial haemolysis (SRH), and microneutralization (MN) assays three weeks after each vaccination. Vaccine safety was assessed throughout the study.

Results

Analysis by HI assay found that two doses of MF59-H5N1 resulted in a seroconversion rate of 56% and a geometric mean ratio (GMR) of 7.1 in adult subjects. Similar results were observed on analysis by SRH (GMR 4.03; seroconversion 78% and seroprotection 91%) and MN (seroconversion 67%) assays. These data met the European licensure criteria for influenza vaccines. No significant difference in immunogenicity was detected between the adult and elderly populations. Anti-A/H5N1 cross-clade antibodies were detected by SRH, 49% of adult and 32% of elderly subjects achieved seroconversion after the second vaccine dose. Overall, MF59-H5N1 containing 7.5 μg antigen was less reactogenic than the MF59-adjuvanted trivalent seasonal vaccine which contained 15 μg antigen for each component strain.

Conclusions

Two doses of MF59-H5N1 vaccine were well tolerated and induced adequate levels of seroprotection against homologous and cross-clade A/H5N1 virus. These data support the suitability of MF59-adjuvanted A/H5N1 vaccine for pre-pandemic use in adults and the elderly.     

Increasing adolescent immunization by webinar: a brief provider intervention at federally qualified health centers

Objective

To evaluate a brief intervention to increase provision of adolescent vaccines at health centers that reach the medically underserved.

Method

In April 2010, clinical coordinators from 17 federally qualified health centers (serving 7827 patients ages 12–17) participated in a competition to increase uptake of recommended adolescent vaccines: tetanus, diphtheria, and pertussis booster; meningococcal conjugate; and human papillomavirus. Vaccination coordinators attended a webinar that reviewed provider-based changes recommended by the CDC's Assessment, Feedback, Incentives, and eXchanges (AFIX) program and received weekly follow-up emails. Data on vaccine uptake came from the North Carolina Immunization Registry.

Results

Uptake of targeted adolescent vaccines increased during the one-month intervention period by about 1–2% (all p < .05). These small but reliable increases were greater than those observed for non-targeted vaccines (measles, mumps, and rubella; hepatitis B; and varicella).

Conclusion

This AFIX webinar led to small increases in provision of targeted adolescent vaccines over a one-month period. Similar, sustainable programs at healthcare facilities, including federally qualified health centers that function as safety net providers for medically underserved populations could help reach populations with great need.     

Development of VAX128, a recombinant hemagglutinin (HA) influenza-flagellin fusion vaccine with improved safety and immune response

Background

We evaluated the safety and immunogenicity profiles of 3 novel influenza vaccine constructs consisting of the globular head of the HA1 domain of the Novel H1N1 genetically fused to the TLR5 ligand, flagellin. HA1 was fused to the C-terminus of flagellin in VAX128A, replaced the D3 domain of flagellin in VAX128B and was fused in both positions in VAX128C.

Methods

In a dose escalation trial, 112 healthy subjects 18–49 and 100 adults ≥65 years old were enrolled in a double blind, placebo controlled clinical trial at two centers. Vaccines were administered IM at doses ranging from 0.5 to 20 μg. VAX128C was selected for second study performed in 100 subjects 18–64 years old comparing 1.25 and 2.5 μg doses. All subjects were followed for safety and sera collected pre- and post-vaccination were tested by hemagglutination-inhibition (HAI). Serum C-reactive protein and cytokine levels were also measured.

Conclusions

In the first study high HAI titers and high seroconversion and seroprotection rates were observed at doses ≥2.5 μg in adults 18–49. In adults ≥65 years, the vaccines doses of ≥4 μg were required to induce a ≥4-fold rise in HAI titer, 50% seroconversion and 70% seroprotection. Based on safety, VAX128A was tested up to 8 μg, VAX128B to 16 μg and VAX128C to 20 μg. Dose escalation for VAX128A was stopped at 8 μg because one subject had temperature 101.6 °F associated with a high CRP response, VAX128B was stopped at 16 μg because of a severe AE associated with a high CRP and IL-6 response. VAX128C was not stopped before reaching the 20 μg dose. In the second study VAX128C was well tolerated among 100 subjects who received 1.25 or 2.5 μg. The peak GMT was 385 (95%CI 272–546), 79% (71–87%) seroconversion and 92% (84–96%) seroprotection.

Discussion

Flagellin adjuvanted vaccines can be designed to minimize reactogenicity and retain immunogenicity, thereby representing a promising next generation vaccine technology.     

Clinical aspects and outcome of suspected severe pediatric malaria

Objective

The authors had for aim to evaluate diagnosis and treatment practices applied to children with clinically suspected severe malaria, in two referral hospitals of Kisangani.

Patients and methods

A prospective study was carried out between January 1, 2010 and February 28, 2011 including all children admitted for clinically suspected severe malaria, with at least one of the WHO severity criteria.

Results

One thousand one hundred and fifty-four children were admitted in the two hospitals, 427 (37.0%, n = 1.154) for clinically suspected severe malaria: 155 (36.3%, n = 427) had a positive thick drop examination (TDE), 198 (46.4%, n = 427) a negative one, and 74 (17.3%, n = 427) without thick blood smear examination. Prostration (48.0%) and anemia (40.3%) were the most common severity criteria, while 14.5% and 9.8% presented with convulsions and impaired consciousness respectively. The etiological treatment was quinine infusion. The case specific fatality rate was 19.4% (n = 427), 7.7% (n = 155) in confirmed cases, 9.6% (n = 198) in patients with negative thick blood smear, and 70.3% (n = 74) in patients without any TDE (P < 0.001).

Conclusion

Poor technical support and inadequate organization of the patient circuit can result in underestimating the metabolic complications of severe malaria and of other severe infections of early childhood. This is detrimental to the patients, even when effective drugs are available.     

Assessment of the immunogenicity and safety of varying doses of an MF59®-adjuvanted cell culture-derived A/H1N1 pandemic influenza vaccine in Japanese paediatric, adult and elderly subjects

Introduction

Effective vaccination strategies are required to combat future influenza pandemics. Here we report the results of three independent clinical trials performed in Japan to assess the immunogenicity, tolerability and safety of varying doses of a cell culture-derived MF59^®-adjuvanted A/H1N1 pandemic vaccine in healthy Japanese paediatric, adult and elderly subjects.

Methods

One hundred and twenty-three children (6 months–18 years), and 200 adults (19–60 years) were randomly assigned in a 1:1 ratio to receive two doses of vaccine containing either 7.5 μg antigen with a full (9.75 mg) adjuvant dose, or 3.75 μg antigen with a half (4.875 mg) adjuvant dose. One hundred elderly (≥61 years) subjects received only the low antigen/adjuvant vaccine formulation. Immunogenicity was assessed by haemagglutination inhibition assay at baseline and three weeks after the first and second vaccine doses on Days 22 and 43, respectively. Solicited and unsolicited adverse reactions were recorded for seven and 21 days post-immunization, respectively.

Results

In adult and elderly subjects, a single low antigen/adjuvant dose vaccination was sufficient to meet all of the three European licensure criteria established for influenza vaccines. One high, or two low antigen/adjuvant dose vaccinations were required to meet the licensure criteria in paediatric subjects. Both vaccine formulations were well tolerated, with the majority of adverse reactions mild to moderate in severity. None of the five serious adverse events reported throughout the three trials were considered to be vaccine-related by the investigators.

Conclusion

The use of MF59 adjuvant allows for much reduced vaccine antigen content, and a single dose administration schedule in adults and the elderly. The production of pandemic vaccine using modern cell culture techniques is highly advantageous in terms of the quantity, quality, and rapidity of antigen production; these benefits, in combination with the use of MF59, maximize manufacturing capacity and global vaccine supply. These data support the suitability of the investigational vaccine for use in the Japanese paediatric, adult, and elderly populations.     

Synthetic Influenza vaccine (FLU-v) stimulates cell mediated immunity in a double-blind, randomised, placebo-controlled Phase I trial

Objectives

Current Influenza vaccines elicit antibody mediated prophylactic immunity targeted to viral capsid antigens. Despite their global use these vaccines must be administered yearly to the population, cannot be manufactured until the circulating viral strain(s) have been identified and have limited efficacy. A need remains for Influenza vaccines addressing these issues and here we report the results of a Phase Ib trial of a novel synthetic Influenza vaccine (FLU-v) targeting T cell responses to NP, M1 and M2.

Methods

Forty-eight healthy males aged 18–40 were recruited for this single-centre, randomised, double blind study. Volunteers received one single low (250 μg) or high (500 μg) dose of FLU-v, either alone or adjuvanted. Safety, tolerability and basic immunogenicity (IgG and IFN-γ responses) parameters were assessed pre-vaccination and for 21 days post-vaccination.

Results

FLU-v was found to be safe and well tolerated with no vaccine associated severe adverse events. Dose-dependent IFN-γ responses >2-fold the pre-vaccination level were detected in 80% and 100% of volunteers receiving, respectively, the low and high dose adjuvanted FLU-v formulations. No formulation tested induced any significant FLU-v antibody response.

Conclusion

FLU-v is safe and induces a vaccine-specific cellular immunity. Cellular immune responses are historically known to control and mitigate infection and illness during natural infection.     

Safety of live, attenuated oral vaccines in HIV-infected Zambian adults: Oral vaccines in HIV

Background

Current recommendations are that HIV-infected persons should not be given live vaccines. We set out to assess potential toxicity of three live, attenuated oral vaccines (against rotavirus, typhoid and ETEC) in a phase 1 study.

Methods

Two commercially available oral vaccines against rotavirus (Rotarix) and typhoid (Vivotif) and one candidate vaccine against Enterotoxigenic Escherichia coli (ACAM2017) were given to HIV seropositive (n = 42) and HIV seronegative (n = 59) adults. Gastrointestinal symptoms were sought actively by weekly interview up to 1 month of vaccination. In rotavirus vaccine recipients, intestinal biopsies were collected by endoscopy and evaluated for expression of IL-8 and pro-inflammatory cytokines.

Results

No difference was observed between symptoms in HIV infected and HIV uninfected vaccinees, except for diarrhoea reported more than 7 days after the last dose of vaccine. If only diarrhoea episodes within 7 days of vaccination are included, diarrhoea was not more frequent in HIV seropositive than in HIV seronegative vaccinees (OR 6.7, 95% CI 1.2–67; P = 0.09). However, if later episodes of diarrhoea are included, a significant increase in diarrhoea was demonstrated (OR 5.3, 95% CI 0.98–53; P = 0.04). All episodes were mild and transient. IL-8 was slowly up-regulated over the week following vaccination (P = 0.02), but IL-β, IFNγ or TNFα were not.

Conclusions

No evidence was found of adverse events following administration of these three vaccines, except for late episodes of diarrhoea which may not be attributable to vaccination. Our data do not support the need for a prohibition on oral administration of live, attenuated vaccines to all HIV infected adults, though further work on severely immunocompromised adults and children are required.     

Population-based surveillance for invasive pneumococcal disease and pneumonia in infants and young children in Goiânia, Brazil

Background

Streptococcus pneumoniae is the leading cause of vaccine-preventable death in children <5 years of age globally. We determined incidence rates of invasive pneumococcal disease (IPD), clinical and chest X-ray-confirmed pneumonia (CXR + Pn), S. pneumoniae serotype distribution, and antimicrobial susceptibility in children in Goiânia, Brazil.

Methods

Prospective, population-based surveillance was conducted from May 2007 to May 2009 in children 28 days to <36 months of age presenting to all 33 pediatric healthcare services (outpatient departments, emergency rooms, hospitals) in Goiânia. Eligibility criteria were temperature ≥39.0 °C in the previous 24 h and/or clinical suspicion of pneumonia or IPD.

Results

14,509 subjects were enrolled. Median age was 14.0 months. S. pneumoniae was detected in 64 samples from 62 subjects: 58 (90.6%) blood; 4 (6.3%) cerebrospinal fluid; and 2 (3.1%) pleural fluid. Incidence rate of IPD (culture- and polymerase chain reaction-positive) for all children aged 28 days to <36 months was 57.5/100,000; overall incidence for culture-positive only was 54.9/100,000. Age stratification of culture-positive-only subjects found the highest rates were, 114.6/100,000 and 69.8/100,000, respectively, for the 6 months to <12 months and 12 months to <24 months age groups. The overall incidence of invasive pneumonia and pneumococcal meningitis was 37.2/100,000 and 5.3/100,000, respectively. The most common IPD serotypes were 14 (45.0%), 6B (13.3%), 18C (6.7%), and 23F (5.0%). Eight isolates (13.3%) were penicillin nonsusceptible. The cumulative percentages of serotypes included in 7-valent, 10-valent, and 13-valent pneumococcal conjugate vaccines were 78.3%, 80.0%, and 88.3%, respectively. The overall incidence of clinical pneumonia and CXR + Pn was, 9598/100,000 and 3428/100,000, respectively. CXR + Pn rates for hospitalized and non-hospitalized subjects were 1751/100,000 and 1677/100,000, respectively.

Conclusions

The burden of IPD and pneumonia is considerable in children in a large Brazilian city, and is seen in hospitalized as well as ambulatory subjects. Vaccination with pneumococcal conjugate vaccines has the potential to decrease this burden.