Pneumococcal vaccination in Infant @ 3,5 12month

Immunogenicity and Tolerability of a Heptavalent Pneumococcal Conjugate Vaccine Administered at 3, 5 and 12 Months of Age

Käyhty, Helena PhD; Åhman, Heidi PhD; Eriksson, Karin; Sörberg, Mikael MD, PhD; Nilsson, Lennart MD, PhD

Published: 03/22/2005

Abstract
Background: The recommended vaccination schedule for the pneumococcal conjugate vaccine (PCV) includes 4 immunizations, according to the national programs in the United States and some European countries. Other countries use a national schedule for routine vaccinations in early childhood that includes only 3 doses.
Aims: The goals were to assess the immunogenicity and tolerability of PCV with a vaccination schedule that included 3 doses during the first 1 year of life (a 2+1 dose schedule) and to determine the immune responses to concomitantly administered Haemophilus influenzae type b (Hib) vaccine.

Methods: A total of 101 healthy Swedish infants were enrolled in an open, nonrandomized, multicenter study. PCV was administered concomitantly with (at separate sites) a diphtheria-tetanus toxoids-acellular pertussis vaccine, inactivated polio vaccine and Hib conjugate vaccine combination at 3, 5 and 12 months of age. IgG antibody concentrations for the 7 serotypes included in the PCV and the Hib capsular polysaccharide in serum samples taken at 3, 6, 12 and 13 months were determined with enzyme immunoassays. Local and systemic reactions were monitored for 3 days after each immunization, and serious adverse reactions were monitored for the whole study period.

Results: Two doses of PCV induced satisfactory antibody responses, with the exception of serotypes 6B and 23F. The third dose evoked strong responses for all serotypes, which suggests good immunologic priming with the primary series of 2 doses. The mean anti-Hib antibody concentrations were similar to those noted in earlier studies among Swedish children. The PCV was well tolerated.

Conclusion: The pneumococcal antibody concentrations at 13 months were comparable with those noted previously with the 4-dose schedule. The results suggest that the implementation of a 2+1 dose schedule for PCV should be considered.

Introduction
Several pneumococcal conjugate vaccines (PCVs) have been tested in clinical trials,[1] and a heptavalent PCV, which has been licensed in many parts of the world, is in wide use in the United States[2] and in some European countries. With serotype-specific efficacy of 97% against invasive disease,[3] the present PCV could cover 65-80% of invasive pneumococcal disease in Europe.[4-7] The postlicensure follow-up data have shown that the vaccination program has had a marked impact on the incidence of invasive pneumococcal disease in the United States.[2,8] In addition, vaccination with a PCV could decrease the spread of antibiotic-resistant pneumococci.[9] Heptavalent PCVs have shown efficacy of 56-57% against acute otitis media caused by the vaccine serotypes[10,11] and have reduced the number of ear tube replacements by 24 and 44% in the United States[12] and in Finland,[13] respectively. In South Africa and the United States, the protective effect on x-ray-positive pneumonia has been approximately 20%.[14,15]

The vaccination schedule recommended for PCV, and the one used in most previous clinical studies, includes 4 immunizations (ie, the 3+1 schedule, with a 3-dose primary series in 6 months, followed by a fourth dose in the second year) according to the national vaccination programs in the United States and some European countries. The vaccination program for infants in Sweden, Denmark, Norway and Italy, as well as Finland beginning in 2005, is based on primary vaccinations at 3 and 5 months and a third dose at 12 months of age (ie, the 2+1 schedule). The only feasible schedule for the PCV would involve concomitant administration with other childhood vaccines. In addition, decreasing the number of PCV injections would decrease costs and would thus facilitate addition of the PCV to national vaccination programs.

The primary aim of this study was to assess the immunogenicity and tolerability of a heptavalent PCV after primary vaccination consisting of 2 doses (administered at 3 and 5 months of age), with a third dose given at 12 months of age. Our secondary aim was to determine the concentrations of antibody to Haemophilus influenzae type b (Hib) after the second and third doses of the Hib conjugate vaccine, which was given concomitantly with the PCV.

Discussion
We showed that the heptavalent PCV was immunogenic and well tolerated when given with a 2+1 schedule concomitantly with a DTaP-IPV/Hib combination vaccine. At the age of 6 months, 1 month after the second dose, the antibody concentrations were already clearly elevated for all serotypes; nonetheless, the concentrations remained low for serotypes 6B and 23F, compared with the other serotypes. This was not surprising, because these serotypes evoked the lowest responses after 2 doses in the previous studies with the same or other vaccines.[16,17,20,24,25] The antibody concentrations increased significantly after the third vaccination, especially for serotypes 6B and 23F. This indicates good immunologic priming after 2 doses of PCV. On the basis of experience with the Hib conjugate vaccine,[26,27] it is thought that immunologic priming, in addition to existing antibody concentrations, is important for long-lasting protection. This is probably true also for PCVs. In fact, antibody concentrations that were lower after 3 doses of a PCV than those measured in this study after 2 doses provided protection against acute otitis media caused by serotypes 6B and 23F[11] among 6- to 12-month-old infants. We think that the immune response detected in this study would provide protection against invasive pneumococcal disease between the ages of 6 and 12 months.

The administration of PCV concomitantly with the DTaP-IPV/Hib combination vaccine did not seem to affect the immune response to Hib conjugate vaccine. The mean anti-Hib antibody concentrations remained low after the second dose but were not different from those reported from other studies with this vaccination schedule in Sweden.[28,29] Despite the low antibody responses of Swedish children after the second administration of the Hib vaccine, the incidence of Hib disease has remained low and breakthrough cases have been rare with this schedule.[30]

Fever (usually mild) was quite common and was observed more often after the third dose than after the first dose. Fever was observed slightly more often than in a similar study in Germany in which the same PCV was administered concurrently with the same DTaP-IPV/Hib combination vaccine but at 2, 3, 4 and 11-15 months of age. In that study, fever of ≥ 38ºC was observed for 29-48.2% of subjects, depending on age, and high fever of ≥ 39ºC was noted for 2.9-8.3%.[31] In the German study, fever was more common after the first vaccination in the PCV-treated group than in the control group that received only the combination vaccine but was equivalent between the groups after the subsequent vaccinations. In this study, we cannot tell how much the PCV contributed to the low-grade fever, because no control group was included. However, it has been shown that acellular pertussis vaccines induce higher rates of nodules and fever after the second or third vaccination than after the first dose.[32]

Because the PCV has been licensed in many areas of the world, requiring placebo-controlled efficacy trials with novel PCVs, PCV formulations or schedules is no longer realistic. The licensure of new PCVs and the acceptance of new PCV schedules will depend on phase II studies of immunogenicity and safety, which should be planned to show noninferiority to the licensed vaccine or to an established vaccination schedule.21 Although this study was not planned as a noninferiority study, we can compare the data of this study with the published immunogenicity data from efficacy trials with 2 different endpoints, i.e. invasive disease or acute otitis media. In these trials, the same PCV as in this study was used but with the recommended 4-dose schedule. The GMC values for the serotype-specific antibodies from this study were compared with those from 2 trials that demonstrated that the vaccines are efficacious, i.e. the Northern California Kaiser-Permanente study3 and the Finnish Otitis Media (FinOM) Vaccine Trial10 ( Table 3 ). Furthermore, we compared the distribution of antibody concentrations in this study and in the FinOM trial arm that used the same cross-reactive material-conjugated PCV (Figs. 1 and 2). Sera from the FinOM trial and from this study were analyzed in the same laboratory, whereas the U.S. data came from the Wyeth laboratories. Interlaboratory comparisons have proved that the 2 laboratories give concordant results.

The GMC values measured in this study after the second dose were comparable with those noted in the efficacy trials after 3 doses. The only exception was serotype 6B, for which the GMC values in this study were lower than those measured in the Finnish and U.S. studies ( Table 3 ). For serotype 23F, the concentrations remained lower than those in the Finnish study but were not markedly lower than those in the U.S. study. Furthermore, the distributions of antibodies (Fig. 1) and the proportions of infants with concentrations of =0.35 µg/mL in this study were different from those in the FinOM study for these 2 serotypes only. In addition, except for serotype 6B, the concentrations after 2 doses were comparable with those seen after the third dose among German infants who had received PCV concomitantly with DTaP-IPV/Hib combination vaccine at 2, 3 and 4 months.[31]

At 13 months, 1 month after the third dose of PCV, antibody concentrations measured in this study were as high as those in the previous Finnish, U.S. ( Table 3 ) and German[31] studies and were distributed similarly with respect to those measured in the previous Finnish study after 4 doses (Fig. 2), indicating equally good immunologic priming after 2 or 3 doses in early infancy. Other surrogate measures of immunologic priming, such as antibody avidity determinations or challenge with pneumococcal PS vaccine,[21] should be used in the future to confirm this.

Several studies with conjugate vaccines among infants yielded results concordant with this study. Even 1 dose of group C meningococcal vaccine[33] or Hib conjugate vaccine[34] at 2 months of age could induce good immunologic priming. In addition, a South African study with a nonavalent PCV showed that the antibody concentrations for 7 of the 9 vaccine serotypes were elevated even after the first dose of the PCV, given at the age of 6 weeks.[24] A Filipino study showed that 1 dose of an 11-valent PCV administered at the age of 18 weeks induced an immune response comparable with that measured after 3 doses administered at 6, 10 and 14 weeks.[35] Finally, preliminary data from a U.K. study indicate similar immunity after 2 or 3 doses of PCV in early infancy.[36]

The PCV has now been incorporated into the universal vaccination program for U.S. children. In other parts of the world, however, vaccination with PCV is still uncommon. There might be several reasons for this. First, the licensed vaccine contains 7 serotypes that are the most prevalent for invasive pneumococcal disease in the United States. They cover > 90% of the pneumococcal invasive disease burden of U.S. children,[37] but it is not yet clear how good the coverage would be in other parts of the world. Second, the price of the PCV ($40-50 per dose) has made it difficult to include the vaccine in programs that are paid for by the public health sector, even in the industrialized world. Third, the PCV is licensed for use among young children with a 4-dose schedule (3+1 schedule). Adoption of the PCV in countries that use 2+1 childhood immunization schedules would be easier and cheaper if the vaccine could be given concomitantly with other vaccines. The preliminary postmarketing surveillance reports from the United States suggest that 2 doses in the primary series are sufficient for protection,[38] although additional information on the duration of protection is needed. In conclusion, the immunogenicity data from this and other studies[24,35,36] suggest that the use of fewer than 4 doses is a practical option for administration of the PCV.

full article : http://www.medscape.com/viewarticle/500758_4