Fred Zepp

Comparison of the immunogenicity and safety of Cervarix™ and Gardasil® human papillomavirus (HPV) cervical cancer vaccines in healthy women aged 18–45 years

This observer-blind study compared the prophylactic human papillomavirus (HPV) vaccines, Cervarix™ (GlaxoSmithKline) and Gardasil® (Merck), by assessing immunogenicity and safety through one month after completion of the three-dose vaccination course. Women (n=1106) were stratified by age (18–26, 27–35, 36–45 years) and randomized (1:1) to receive Cervarix™ (Months 0, 1, 6) or Gardasil® (Months 0, 2, 6). At Month 7 after first vaccination, all women in the according-to-protocol cohort who were seronegative/DNA negative before vaccination for the HPV type analyzed had seroconverted for HPV-16 and HPV-18 serum neutralizing antibodies, as measured by pseudovirion-based neutralization assay (PBNA), except for two women aged 27–35 years in the Gardasil® group who did not seroconvert for HPV-18 (98%). Geometric mean titers of serum neutralizing antibodies ranged from 2.3–4.8-fold higher for HPV-16 and 6.8–9.1-fold higher for HPV-18 after vaccination with Cervarix™ compared with Gardasil®, across all age strata. In the total vaccinated cohort (all women who received at least one vaccine dose, regardless of their serological and DNA status prior to vaccination), Cervarix™ induced significantly higher serum neutralizing antibody titers in all age strata (p

Combined vaccination of Haemophilus influenzae type b conjugate and diphtheria-tetanus-pertussis containing acellular pertussis

After the introduction of effective Haemophilus influenzae type b (Hib) conjugate vaccines, clinical practice has driven the development of combination vaccines comprising Hib conjugates with the infant diphtheria-tetanus-pertussis (DTP) vaccines. However, when such combinations contain an acellular pertussis component (Pa), the antibody response to Hib is lower than that with separate injections and doubts have been raised about their efficacy. We believe that such concerns are unwarranted, since the serological correlates of efficacy previously applied for Hib polysaccharide vaccines seem inappropriate for Hib conjugates. Furthermore, our own studies have shown that the lower antibody responses are not associated with impaired function of the antibodies induced, nor, and possibly more importantly, with the induction of immune memory against Hib. Therefore, with the proviso that careful clinical surveillance of Hib disease is maintained, we encourage the introduction of DTPa-Hib combinations to facilitate the inclusion of Hib into the already crowded childhood immunisation schedule.

Predictability of early atopy by cord blood‐IgE and parental history

Background Atopic family history and cord blood IgE have been used as predictors of atopic disease in newborns for about 20 years, but at least for cord blood IgE the sensitivity has been shown to be very low. The objective of this paper was to evaluate whether parental history and cord blood‐IgE were more accurate predictors for the appropriate atopic phenotypes in the infants rather than for any atopy.

Rationale for pertussis booster vaccination throughout life in Europe

Although the introduction of universal pertussis immunisation in infants has greatly reduced the number of reported cases in infants and young children, disease incidence has been increasing in adolescents and adults in recent years. This changing epidemiological pattern is probably largely attributable to waning immunity after natural infection or vaccination. Furthermore, improved diagnostic testing, active surveillance, changes in disease susceptibility, vaccine characteristics, and increased awareness of the disease might also be contributing factors. Susceptibility to pertussis in adolescents and adults results not only in direct morbidity in these age groups, but also poses a transmission risk to susceptible non-immune infants who are often too young to be vaccinated. Because vaccination schedules vary across Europe, we review the pertussis situation in this region and propose considerations for use of pertussis booster vaccinations at different ages to reduce individual morbidity and transmission from present rates and increase herd protection.

Recommendations are needed for adolescent and adult pertussis immunisation: rationale and strategies for consideration

Pertussis vaccination of infants has dramatically reduced disease, complications and deaths in infancy and early childhood. But there is still a major public health challenge--to deal with the morbidity and economic burden of illness in older children, adolescents and adults. Furthermore, it is these groups that form a major source of infection for non-immunised and partially immunised infants who are at high risk of severe complications. Adult-type acellular pertussis vaccine confers safe and effective protection against pertussis. There are several strategies to consider for immunising older individuals. Universal vaccination of all age groups would be the best available strategy for protecting individuals. It would also reduce the potential for transmitting the disease to other susceptibles, particularly infants. However, such a policy may be difficult both logistically and economically at this time. More easily achievable as a first step would be a strategy of universal adolescent booster vaccination combined with a programme targeted at adults most likely to have contact with very young babies including healthcare and childcare workers, parents and close family contacts. There is also potential for offering vaccination to adults (and their carers and close contacts) whose medical conditions or advanced age may place them at increased risk of more severe pertussis disease. Specific details of immunisation programmes must be made on a country by country basis depending on local circumstances.

Principles of vaccine design - lessons from nature.

Microbial pathogens have developed complex and efficient ways of counteracting and evading innate and adaptive immune mechanisms. The strategies used by pathogens determine strongly the type of immune response a vaccine should elicit and how the vaccine should be formulated. Improved knowledge of immune response mechanisms has brought successes in the development of vaccines that protect against challenging pathogens as well as vaccines that can be used in immunocompromised and elderly populations. This includes the production of highly purified antigens that provide a better reactogenicity and safety profile than some of the early whole-pathogen vaccines. Successful attempts to improve antigen purity, however, can result in weakened immunogenicity. The search for approaches to overcome this has led to new technologies, such as live vector vaccines, DNA vaccines and novel adjuvant formulations, which have been based on growing knowledge of the interplay between innate and adaptive immune systems and the central role played by antigen-presenting cells. Of these technologies, one of the most promising to date is based on the use of innovative adjuvants combined with careful antigen selection. Vaccine design has therefore become more tailored, and in turn has opened up the potential of extending its application in immunotherapies to tackle diseases such as cancer, Alzheimer disease and immune-mediated disorders.

Immunogenicity and safety of two doses of tetravalent measles-mumps-rubella-varicella vaccine in healthy children.

Background: Combination vaccines against common childhood diseases are widely used, provide an improved coverage, are more convenient and are more cost-effective than multiple injections. We conducted a study to evaluate the safety and immunogenicity of acombined measles-mumps-rubella-varicella (MMRV) candidate vaccine in comparison with the separate administration of licensed measles-mumps-rubella (MMR; Priorix) and varicella (V; Varilrix) vaccines. Methods: Healthy children 12–18 months of age received 2 doses of MMRV vaccine (3 lots) 6–8 weeks apart (MMRV group) or 1 dose of MMR vaccine administered concomitantly with 1 dose of varicella vaccine, followed by a second dose of MMR at 6–8 weeks later (MMR+V group). Local symptoms (redness, pain and swelling) were recorded for 4 days after vaccination, and fever (any, axillary temperature ≥37.5°C or rectal temperature ≥38.0°C; grade 3, axillary temperature >39.0°C or rectal temperature >39.5°C) was monitored daily for 15 days. Other adverse events were monitored for 6 weeks. Results: A total of 494 children were vaccinated (371 in the MMRV group and 123 in the MMR+V group. Two doses of MMRV vaccine were at least as immunogenic as 2 doses of MMR and 1 dose of varicella vaccine. After the second dose, all children had seroconverted to measles, rubella and varicella in both vaccine groups, and 98% versus 99% had seroconverted to mumps in the MMRV versus the MMR+V group, respectively. The MMRV vaccine did not induce an increased local or general reactogenicity compared with the separate administration, although a higher incidence of low grade fever was seen after the first dose in the MMRV group (67.7% after MMRV versus 48.8% after MMR+V; P < 0.05), this was not observed for grade 3 fever (11.6% after MMRV versus 10.6% after MMR+V; P = 0.87). After the second dose, no differences in incidence of fever were found in either MMRV or MMR+V groups. Conclusion: Administration of 2 doses of the combined MMRV vaccine was as immunogenic and well-tolerated as separate injections of MMR and varicella vaccine.

Effect of cordycepin on interleukin-10 production of human peripheral blood mononuclear cells.

Therapeutic options for controlling autoimmune diseases are still very limited. Interleukin-10 has been reported to be a promising approach to therapeutic intervention. In the search for a drug which results in the selective upregulation of interleukin-10, we investigated the immunoregulative effects of cordycepin. We have measured interleukin-10 and interleukin-2 secretion of human peripheral blood mononuclear cells that were incubated with cordycepin and assessed the influence of cordycepin on the expression of interleukin-10 mRNA, the proliferative response and the expression of surface markers on T lymphocytes. In addition, the subsets of interleukin-10-secreting cells, the influence of anti-interleukin-10 neutralizing antibody and cytotoxicity of cordycepin were evaluated. Our results suggest that cordycepin has a significantly upregulative effect on interleukin-10 production and interleukin-10 mRNA expression. Interleukin-10-producing cells included in CD4+, CD8+, CD19+, CD56+ and CD14+ cells. At the same time, cordycepin inhibited phytohaemagglutinin-induced interleukin-2 production and proliferation of peripheral blood mononuclear cells. A restricted T lymphocyte activation was also reflected by a reduced expression of the surface markers CD25, CD45RO, CD54, CD71 and HLA DR. Anti-interleukin-10 neutralizing antibody could not completely block the suppressive effect of cordycepin on production of interleukin-2. Cordycepin in the effective concentration presented slight cytotoxicity but did not increase apoptosis. These results indicate that cordycepin exerts immunoregulative effects. Further research on it may provide an approach for the development of novel immunomodulatory drugs which directly alter the secretion of cytokines.

Serum IgE levels during the first 6 years of life.

OBJECTIVE Total serum IgE percentiles were derived for a population-based sample of 4082 white children from Germany by weighted analysis of measurements from the Multicenter Allergy Study cohort. METHODS The children of a prospective birth cohort were selected from a complete 1-year sample of newborns in 6 obstetric departments in 1990. Total IgE was determined at 1, 2, 3, 5, and 6 years of age in 1160 newborns of the cohort. By weighting these measurements for sex, atopic family history, and elevated cord blood IgE, total serum IgE percentiles were estimated for the original population-based sample of 4082 children. RESULTS IgE levels increased by age (P <.0001). We found statistically significant higher total IgE values in boys than in girls at each age (P <.05). Within the group of atopic children, this sex difference was not statistically significant. CONCLUSION Our estimates of total serum IgE levels for a large population-based sample were lower than most values previously reported. We suggest that for both clinical and epidemiologic and genetic studies, IgE values should be expressed with percentiles.

Immunogenicity and reactogenicity of a Haemophilus influenzae type b tetanus conjugate vaccine when administered separately or mixed with concomitant diphtheria-tetanus-toxoid and acellular pertussis vaccine for primary and for booster immunizations

Abstract With an increasing number of new vaccines available for routine childhood immunization, combination vaccines are needed in order to maintain or achieve a high compliance with recommended immunization programmes. In a prospective, randomized, comparative, multi-centre study, 822 healthy infants were enrolled to receive three doses of either a candidate or a commercially available Haemophilus influenzae type b (Hib) vaccine concomitantly with diphtheria-, tetanus- acellular pertussis (DTaP) vaccine. Study subjects were randomly allocated to one of the following groups: (1) separate, or (2) mixed injection of DTaP and candidate Hib vaccine, or (3) separate injection of DTaP and commercial Hib vaccine. One year later the first 189 study subjects received either separate or mixed injections of the same Hib and DTaP vaccines as booster doses. Evaluation of reactogenicity was based on diary cards completed by parents. Immunogenicity was documented by measuring IgG antibody concentrations in serum samples taken before and 4 weeks after primary and booster vaccination. No serious adverse events occurred and most local and systemic reactions were mild to moderate. Booster doses were more reactogenic than primary doses with all groups. Antibody concentrations against pertussis antigens were similar to those seen with DTaP alone. All but one subject had protective antibody concentrations against diphtheria and tetanus. Primary immune response to the Hib vaccine was significantly lower in the group receiving the mixed Hib-DTaP vaccine, however, ≥95% of vaccinees had anti-Hib antibody concentrations ≥0.15 μg/ml and there was a marked booster response (>100-fold) in all groups. Conclusions Mixing DTaP and Hib vaccines for primary immunization caused a decrease in anti-Hib antibody response, although after primary immunization as after booster doses, all subjects showed antibody concentrations considered to be protective for invasive Hib disease. Mixing of the vaccines did not result in increased reactogenicity.