Febrile events including convulsions following the administration of four brands of 2010 and 2011 inactivated seasonal influenza vaccine in NZ infants and children: the importance of routine active safety surveillance

Objective

To evaluate and compare rates of febrile events, including febrile convulsion, following immunisation with four brands of inactivated 2010 and 2011 influenza vaccine in NZ infants and children.

Design

Retrospective telephone surveys of parents of infants and children who received at least one dose of the vaccines of interest.

Setting

184 NZ General Practices who received the vaccines of interest.

Participants

Recipients of 4088 doses of trivalent inactivated vaccines Fluvax^®, Vaxigrip^®, Influvac^® and Fluarix^® and/or monovalent Celvapan. Vaccinees were identified via the electronic Practice Management System and contacted consecutively.

Main outcome measures

Primary outcome was febrile convulsive seizure. Secondary outcomes were presence of fever plus other organ system specific symptoms.

Results

The parental response rate was 99%. Of 4088 doses given, 865 were Fluvax^®, 2571 Vaxigrip^®, 204 Influvac^®, 438 Fluarix^® and 10 Celvapan. Three febrile convulsions followed Fluvax^®, a rate of 35 per 10,000 doses. No convulsions occurred following any dose of the other vaccines. There were nine febrile events that included rigors, all following Fluvax^®. Fever occurred significantly more frequently following administration of Fluvax^® compared with the other brands of vaccines (p < 0.0001) and Fluvax recipients were more likely to seek medical attention. Influvac^® also had higher rates of febrile reactions (OR 0.54, 0.36–0.81) than the other two brands Vaxigrip^® (OR 0.21, 0.16–0.27) and Fluarix^® (OR 0.10, 0.05–0.20). After multivariable analysis vaccine, European ethnicity and second dose of vaccine were significantly associated with reporting of fever within 24 h of vaccination.

Conclusions

Influenza vaccines have different rates of reactogenicity in children which varies between ethnic groups. High rates of febrile convulsions and reactions in children receiving Fluvax^® and to a lesser extent the higher fever rates in those receiving Influvac^® compared with the other two brands of influenza vaccines in this study suggests that reactogenicity profiles need to be considered prior to national policy advice each season. The risk-benefit profile in children might not be equally favourable for all licensed paediatric influenza vaccines. More attention needs to be given to comparative research for all trivalent seasonal vaccines, and with all strain changes.     

Allergic patients with and without allergen-specific immunotherapy mount protective immune responses to tick-borne encephalitis vaccination in absence of enhanced side effects or propagation of their Th2 bias

BackgroundAllergic diseases are caused by Th2-driven immune responses and their treatment with specific immunotherapy (SIT) leads to immunomodulation via IL10, TGF-ß and Th1/Tr1 shift. This phase IV, open-label clinical trial investigated whether allergies and SIT treatment influenced immune responses to routine vaccination.MethodsWe studied three groups: 49 allergic patients (allergic group), 21 allergic patients receiving maintenance doses of SIT (SIT group), and 49 non-allergic controls. All subjects received tick-borne encephalitis (TBE) booster vaccines and humoral and cellular immune responses were evaluated after one week, four weeks and six months.ResultsThe levels and kinetics of neutralizing TBE-specific antibodies, reflecting protection against TBE, were not significantly different in the three groups. The allergic group showed Th2 polarization pre-booster as indicated by increased TBE-specific IgG1 and elevated mitogen-induced IL5 production. Alum-adjuvanted TBE vaccine led to Th2 biased immune responses in the controls, but to no further enhancement of Th2 polarization in the allergic and SIT group. Furthermore, in the SIT group cellular parameters reflected the induction of immunomodulation due to increased Tregs, elevated baseline IL10 and lack of TBE-specific IL5. Importantly, these cellular regulatory responses did not limit the ability to mount sufficient TBE-specific antibodies after the booster. All groups tolerated the vaccine well with no exacerbation of allergic symptoms.ConclusionTBE booster vaccinations were immunogenic and safe in both the allergic and SIT group and contributed to balanced immune responses. Our data indicate that all allergic patients, even when undergoing SIT, should be vaccinated without hesitation and at regular intervals according to standard recommendations.ClinicalTrials.gov (NCT02511535).     

Characterization and clinical evaluation of live influenza a vaccine prepared from a recombinant of the A/USSR/92/77 (H1N1) and the cold-adapted A/Ann Arbor/6/60 (H2N2) strains

Live influenza vaccine was prepared after genetic recombination of the A/USSR/92/77 (H₁N₁) strain with the cold-adapted A/Ann Arbor/6/60 (H₂N₂) strain. The recombinant contains the genes coding for the HA and NA proteins from the A/USSR/92/77 (H₁N₁) strain and the genes coding for the P₁, P₂, P₃, NP, M and NS proteins from the A/Ann Arbor/6/60 (H₂N₂) strain. To assess the properties of this vaccine, it was administered under double-blind conditions to 14 healthy volunteers, while another 14 healthy volunteers received placebo.The vaccine virus appeared to be sufficiently attenuated. No febrile reactions were observed. The vaccinees showed an increase in mean serum haemagglutination-inhibiting antibody level from 19 to 73 after two vaccinations. From nasal swabs and antibody responses, it was concluded that the vaccine virus showed no transmission to the placebo group under conditions of close contact. Also, the vaccine virus was found to be genetically stable.It is concluded that this live influenza virus vaccine meets the requirements for safe use in humans. However, several problems still exist which may impede a general use of live influenza vaccines.     

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.     

Increased reactions to pediatric influenza vaccination following concomitant pneumococcal vaccination

Please cite this paper as: Van Buynder et al. (2013). Increased reactions to pediatric influenza vaccination following concomitant pneumococcal vaccination Influenza and Other Respiratory Viruses 7(2) 184–190. Background Influenza in children causes significant morbidity and hospitalizations and also some mortality particularly in children <5 years of age. Influenza vaccination in children has been shown to be safe and effective, but in 2010 the pediatric influenza vaccination program was suspended in Western Australia after the rate of febrile convulsions observed (9/1000 doses) was 55 times the previously reported rate. In 2009, over 80% of all children in New Brunswick were vaccinated with an adjuvanted monovalent H1N1 vaccine shown to have very high effectiveness, raising the prospect of potential hyper‐responsiveness because of residual protection. We conducted enhanced post‐marketing surveillance to monitor local and general reactions. Methods Parents of participating children seen at dedicated vaccination clinics were given influenza vaccine survey kits to record local and general symptoms up to 3 days following receipt of season influenza vaccine. Results Febrile reactions of ≥38° occurred in <10% of children who received a first dose of seasonal influenza vaccine (n = 660) and severe febrile incidents with fever ≥39° were uncommon. Concurrent administration of other vaccine(s) including conjugated pneumococcal vaccine appeared to increase reactogenicity. No child in the study had a febrile convulsion. Conclusion Influenza vaccines in children are safe, and this study provides a baseline for rapid assessment studies at the start of a vaccine season. Parents should be aware of increased fevers with concurrent vaccine administration, and antipyretics should be considered.     

Multiple-dose granulocyte-macrophage-colony-stimulating factor plus 23-valent polysaccharide pneumococcal vaccine in patients with chronic lymphocytic leukemia: a prospective, randomized trial of safety and immunogenicity

BACKGROUND: For the current study, the authors sought to determine whether administration of multiple-dose granulocyte-macrophage-colony-stimulating factor (GM-CSF) could improve response to standard 23-valent polysaccharide pneumococcal vaccine (PPV) in patients with chronic lymphocytic leukemia (CLL). METHODS: Patients were allocated randomly to receive PPV either alone or with 3 doses of GM-CSF (250 microg) given before or after vaccination. Serum was obtained before, 4 weeks after, and 12 weeks after vaccination for antibody determination. Thirty-two patients with CLL were given PPV. They were randomized to receive 3 doses of GM-CSF either before or after vaccination or to receive no GM-CSF. RESULTS: A 4-fold rise in immunoglobulin G (IgG) to capsular polysaccharides from Streptococcus pneumoniae types 4, 6B, 9V, 14, 19F, and 23F occurred in <10% of patients in each of the 3 groups. There were no differences in geometric mean IgG levels in any of the 3 groups 4 weeks or 12 weeks after vaccination. CONCLUSIONS: In patients with CLL, the response to pure polysaccharide pneumococcal vaccine was low despite immune enhancement with multiple doses of GM-CSF. In all patients, reactogenicity was minor.     

A localizing nanocarrier formulation enables multi-target immune responses to multivalent replicating RNA with limited systemic inflammation

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