Polyribosylribitol Phosphate Research Articles

Experience with the prevention of invasive Haemophilus influenzae type b disease by vaccination in Alaska: The impact of persistent oropharyngeal carriage

Objectives: To report the epidemiology of invasive Haemophilus influenzae type b (Hib) disease in high-risk Alaska Native infants before and after universal infant Hib vaccination and evaluate an increase in invasive Hib disease in 1996 after changing Hib vaccine type. Study design: Statewide laboratory surveillance for invasive Hib disease has been conducted since 1980. Three cross-sectional Hib carriage studies were conducted in 1997 and 1998. Results: The invasive Hib disease rate in Alaska Natives decreased from 332 cases per 100,000 children <5 years old in 1980-1991 to 17:100,000 in 1992-1995 but increased primarily in rural areas to 57.9:100,000 after a switch in Hib vaccine types. Carriage studies in 5 rural Alaska Native villages showed oropharyngeal Hib carriage as high as 9.3% in children aged 1 to 5 years; in contrast, carriage in urban Alaska Native children was <1%. Conclusions: Although Hib disease has decreased in Alaska, the rate of Hib disease and carriage in rural Alaska Natives did not decrease to the same extent as in non-Natives and urban Alaska Natives. Use of polyribosylribitol phosphate–outer-membrane protein conjugate vaccine for the first vaccine dose is critical to disease control in this population with continued transmission in infants <6 months of age. The ability to eliminate Hib carriage and disease may be affected by population characteristics, vaccination coverage, and Hib vaccine type used. This may pose a challenge to global elimination of Hib. (J Pediatr 2000;137:313-20)

Vaccines: World Health Organization versus Federal Drug Administration recommended formula

Vaccines produced in accordance with WHO formulas, differ in concentration from those used in United States according to FDA formulas. We aimed to compare the immunogenicity of both formulas. Infants who were 6 weeks old were randomly put into 3 groups to receive 3 doses of vaccines at 6 weeks, 3 months and 5 months of age. The vaccines consisted of Haemophilus influenzae type b vaccine, diphtheria-tetanus-pertussis and oral polio vaccine. Antibody levels for polyribosylribitol phosphate (PRP), tetanus, diphtheria and poliovirus were measured 1 month after the third dose of vaccines. Although diphtheria and tetanus antigens in the FDA formula are half the concentration of the WHO formula, anti-tetanus and anti-diphtheria antibodies were significantly higher. No difference was found between groups regarding oral poliovirus vaccine.

Associated or combined vaccination of Brazilian infants with a conjugate Haemophilus influenzae type b (Hib) vaccine, a diphtheria–tetanus–whole-cell pertussis vaccine and IPV or OPV elicits protective levels of antibodies against Hib

This study investigated the immunogenicity and safety of including a Haemophilus influenzae type b vaccine (polyribosylribitol phosphate conjugated to tetanus toxoid, PRP-T) in three different vaccination schemes: (1) PRP-T reconstituted with a combined diphtheria–tetanus–pertussis-inactivated poliovirus vaccine (DTP-IPV//PRP-T); (2) PRP-T reconstituted with DTP and administered concomitantly with an oral poliovirus vaccine (DTP//PRP-T+OPV); and (3) PRP-T administered concomitantly with DTP at a different injection site and OPV (DTP+PRP-T+OPV). Vaccines were given at 2, 4, and 6 months of age. A total of 252 infants were enrolled, and randomly assigned to one of the three vaccination groups (84 infants in each group); 241 infants were followed until the end of the study. Antibody production against PRP, diphtheria, tetanus and pertussis antigens was satisfactory for each vaccination scheme used. A good response to Hib vaccine was elicited in each group, and 3 months after the third vaccine dose, at least 97% of children in each group had levels of PRP antibody considered to be seroprotective (>0.15 μg/ml), and over 90% of children in each group had levels over 1.0 μg/ml. The solicited local and systemic adverse events following vaccination were mild in all groups and resolved within 4 days without medical intervention. With the exception of fever, which was more common after the second dose in children who received DTP-IPV//PRP-T, local and systemic reactions did not differ between the vaccination groups. Due to the practical advantages of combined vaccines, their use in routine immunization programs in developing countries is highly desirable. Our results show that Hib conjugate vaccine can be included in routine immunization programs that include either OPV or IPV with satisfactory immunogenicity and safety profiles. This flexible approach should facilitate the inclusion of the Hib conjugate vaccine in routine immunization programs on a world-wide scale.

Quantitation of low level unconjugated polysaccharide in tetanus toxoid-conjugate vaccine by HPAEC/PAD following rapid separation by deoxycholate/HCl

A simple and rapid acid precipitation method has been applied successfully for separating free capsular polysaccharide of Haemophilus influenzae type b (polyribosyl ribitol phosphate, PRP) from PRP–tetanus toxoid conjugate (PRP-T) in a final dosage amount of low-level materials. The unconjugated PRP was found to stay in the supernatant without precipitation, while conjugated PRP-T was fully precipitated. High performance anion exchange chromatography with pulsed amperometric detection (HPAEC-PAD) has been applied for analysis of the PRP content in the supernatant after the separation. This method requires minimum sample handling and is specific, sensitive and reproducible making it suitable for release and stability testing of PRP-T in final containers.

The pathogenic role of fimbriae of Haemophilus influenzae type b in murine bacteraemia and meningitis.

Complement activation and development of murine bacteraemia and meningitis following intranasal instillation of cell-bound fimbriated or non-fimbriated organisms were compared to clarify the role of fimbriae in the pathogenesis of illnesses caused by Haemophilus influenza type b (Hib). In-vitro resistance of non-fimbriate bacteria to the bactericidal effects of normal human serum was at least 400 times greater than that of fimbriate bacteria. The amount of C3 bound to fimbriate Hib was more than that to non-fimbriate Hib. When mice were infected with fimbriate bacteria, 11.5% died. When mice were infected with non-fimbriate bacteria, the mean number of viable organisms gradually increased or was constant up to day 7; 38.5% of these mice died. These in-vivo results were coincident with the in-vitro data. However, the content of polyribosyl ribitol phosphate (PRP) in fimbriate organisms was the same as in non-fimbriate organisms. These results indicate that fimbriate Hib may be less likely to produce bacteraemia and meningitis, correlating with the greater susceptibility to complement-mediated bacteriolysis and the lower mortality seen with this type of organism, although fimbriae increase adherence to epithelial cells (mucosal surface).

Haemophilus influenzae type b conjugate vaccine stability: catalytic depolymerization of PRP in the presence of aluminum hydroxide

The structural stability of the Haemophilus influenzae type b (Hib) capsular polysaccharide, polyribosylribitolphosphate (PRP) in an aluminum hydroxide adsorbed, polysaccharide–protein conjugate vaccine was monitored using modifications of an HPLC assay developed by Tsai et al. [Tsai C-M, Gu X-X, Byrd RA. Quantification of polysaccharide in Haemophilus influenzae type b conjugate and polysaccharide vaccines by high-performance anion-exchange chromatography with pulsed amperometric detection. Vaccine 1993;12:700–706.]. As applied to products containing PRP conjugated to the outer membrane protein complex (OMPC) from Neisseria meningitidis, this assay allows direct measurement of the total PRP content in very complex samples including commercial vaccine products. In addition, with the use of a high-speed centrifugation step, the assay can be used to directly quantify any PRP that is not conjugated to the OMPC carrier protein. These results provide evidence of what appears to be a catalytic reaction taking place between the phosphodiester bond of PRP and the aluminum hydroxide adjuvant that results in hydrolysis of the PRP polymer into smaller chain lengths and liberation of PRP oligomers from the conjugate particle. The reaction approaches an asymptotic limit after approximately two years at 2–8°C. Clinical studies which span this time period confirm that the modest decrease in conjugated PRP content over time does not impact the overall clinical effectiveness of PRP–OMPC-containing vaccines.

Kinetics of Antibody Response to Haemophilus influenzae Type b Vaccines

SummarySerum antibodies to the capsular polysaccharide of Haemophilus influenzae type b (Hib) are effective in preventing or ameliorating invasive disease caused by this human pathogen. Polysaccharide and conjugate (saccharide covalently linked to protein carrier) vaccines have been developed which stimulate the production of such antibodies. The polysaccharide-specific antibody concentrations in the sera of vaccine-naive adults and toddlers on days 1, 3, 7, 14 and 28 following immunisation with one dose of the Hib polysaccharide vaccine (PRP, polyribosylribitol phosphate) or an oligosaccharide-CRM197 conjugate vaccine (HbOC, HibTITER®) were determined. Antibody responses occurred within 7 days of immunisation with the maximum response usually occurring 14 days post-immunisation, irrespective of vaccine or subject age. In this small study, a significant transient decline in pre-existing antibodies was observed only in the groups receiving the polysaccharide vaccine and not in the groups receiving HbOC vaccine. Because of the small magnitude of antigen-specific antibody decline and its transient nature, it is unlikely that this observation has clinical significance.

Reemergence of invasive Haemophilus influenzae type b disease in a well-vaccinated population in remote Alaska.

Before vaccination, Alaska Natives experienced very high rates of invasive Haemophilus influenzae type b (Hib) disease and carriage. Vaccination with Hib conjugate vaccine PRP-OMP (polyribosylribitol phosphate Neisseria meningitidis outer membrane protein) began in 1991 and resulted in a sharp decline in cases. In 1996, after switching to a different Hib conjugate vaccine, DTP-HbOC (which combines diphtheria-tetanus-whole cell pertussis vaccines with HbOC [Hib oligosaccharide CRM197]), cases of invasive Hib disease increased, suggesting ongoing Hib transmission despite widespread vaccination. To determine the prevalence of and risk factors for carriage, a cross-sectional study of oropharyngeal Hib carriage was conducted among Alaska Native children aged 1-5 years in remote southwestern Alaska. Of 496 children with swabs taken, 46 (9.3%) were colonized with Hib. Carriage rates varied by village from 2.2% to 13.2% and by age from 6.1% in 1-year-olds to 14.7% in 5-year-olds. Crowding was associated with Hib carriage. Widespread vaccination with PRP-OMP Hib conjugate vaccine did not eliminate carriage in this population of Alaska Natives, and ongoing carriage contributed to disease resurgence.

Haemophilus influenzae type b conjugate vaccines: a review of efficacy data.

The development of a vaccine against Haemophilus influenzae type b (Hib) was stimulated by its recognition as a major pathogen of early childhood. The first vaccine to be developed was composed of the capsular polysaccharide of the organism, polyribosylribitol phosphate (PRP), and although effective in older children, it failed to protect those <2 years of age, the group with the highest burden of disease. The conjugation of PRP to protein led to a group of vaccines with enhanced immunogenicity and the ability to induce immunologic memory and thus the potential to protect in infancy. To review the trials of Hib conjugate vaccines in which protective efficacy in infants has been assessed and the experience in countries in which Hib conjugate vaccines have been introduced into the routine infant immunization schedule. Each of the Hib conjugate vaccines [PRP-diphtheria toxoid conjugate (PRP-D), PRP conjugated to outer membrane protein of Neisseria meningitidis group B (PRP-OMP), PRP oligosaccharides conjugated to mutant diphtheria toxin CRM197, (HbOC) and PRP conjugated to tetanus toxoid (PRP-T)] has been subjected to prospective clinical trials and all have demonstrated high protective efficacy with one exception: that of the least immunogenic vaccine, PRP-D, when used in a Native American population with a high level of natural disease. The trials have used different populations and different schedules, which limits conclusions about relative efficacies. However, it seems likely that all the vaccines are capable of high efficacy in populations with low levels and late age of Hib disease. Three vaccines (PRP-D, PRP-OMP, PRP-T) have been tested in populations with high rates of disease and only PRP-D has been found lacking. As predicted by immunogenicity data, PRP-OMP affords efficacy after one dose, and PRP-T is efficacious with an accelerated schedule. Of more practical significance the effectiveness of these vaccines when introduced into populations has been uniformly impressive. Particularly where vaccine coverage is high, it is now likely that Hib disease can be eliminated using Hib conjugate vaccines in infancy.

Protective immunogenicity of Haemophilus influenzae type b polysaccharide‐tetanus protein conjugate vaccine in children who failed to respond to prior invasive H. influenzae type b disease

A polyribosylribitol phosphate (polysaccharide)-tetanus protein conjugate vaccine (PRP-T) against Haemophilus influenzae type b (Hib) was evaluated for protective immunogenicity in 25 previously PRP-unimmunized children who had failed to develop protective PRP antibody levels (< 1 microg/ml) after prior invasive Hib disease at median age 10 months. Children under 21 months of age at time of PRP-T immunization received one, two or three doses. Serum was obtained for total PRP antibody, complement mediated bactericidal activity and specific IgG1 and IgG2 PRP antibodies before (n = 25), 1 to 2 months (n = 24) and > 5 months (n = 13) after completed vaccination. One to 2 months after immunization, all but one patient developed > 1 microg/ml of antibody (geometric mean level 50.7 microg/ ml). The non-responder developed protective antibody levels when tested at 6 months after vaccination. Twenty out of 22 sera had detectable complement mediated bactericidal activity (median dilution titer 1:24), 1-2 months after vaccination. Three patients failed to demonstrate PRP antibodies in the IgG1 or IgG2 subclasses, although two of them had protective (> 1 microg/ml) total antibody levels. The second post immunization sera showed persistence of the total PRP antibody levels (geometric mean level 38.2 microg/ml) as well as of the bactericidal activity (median dilution titer 1:32). PRP-T conjugate vaccine is able to elicit a protective immune response in children who have low or unmeasurable PRP antibody levels after a systemic Hib infection.

Reduced response to multiple vaccines sharing common protein epitopes that are administered simultaneously to infants.

The plethora of newly discovered vaccines implies that, in the future, many vaccines will have to be administered simultaneously to infants. We examined the potential interference with the immune response of several coadministered vaccines containing the same protein component, namely, tetanus toxoid (TT). Infants simultaneously receiving a tetravalent pneumococcal vaccine conjugated to TT (PncT) and a diphtheria-tetanus-pertussis-poliovirus-Haemophilus influenzae type b-tetanus conjugate vaccine showed significantly lower anti-H. influenzae type b polysaccharide (polyribosylribitol phosphate [PRP]) antibody concentrations than those receiving either a tetravalent pneumococcal vaccine conjugated to diphtheria toxoid or placebo. A dose range study showed that anti-PRP antibody concentrations were inversely related to the TT content of the PncT vaccines administered in infancy. Postimmunization antitetanus antibody concentrations were also affected adversely as the TT content of the coadministered vaccines was increased. This phenomenon, which we believe derives from interference by a common protein carrier, should be taken into account when the introduction of an immunization program including multiple conjugate vaccines is considered.

Three-year follow-up of vaccine response in extremely preterm infants.

To assess whether the adequate antibody response observed in former extremely premature infants after the primary series of immunizations is sustained after the first booster vaccines. Sixteen former extremely premature (<29 weeks, <1000 g at birth) and 17 former full-term (>37 weeks) infants had sera obtained for antibody titer measurement at 3 to 4 years of age. All had received the primary series and first booster vaccines for diphtheria, pertussis, tetanus, polio, and Haemophilus influenzae type b. Twelve preterm and 14 full-term children had completed the hepatitis B vaccine series. At 3 to 4 years of age, former preterm and full-term children had similar geometric mean titer (GMT) values of antibodies to tetanus, diphtheria, and pertussis. Preterm children had a lower GMT value of Haemophilus polyribosylribitol phosphate (PRP) antibody than did full-term children (0.99 vs 3.06 microg/mL). Fifty percent of preterm and 88% of full-term children had PRP antibody >1.0 microg/mL; 100% of preterm and 94% of full-term children had anti-PRP titers >0.15 microg/mL. GMT values of neutralizing antibodies to polio serotypes 1 and 2 were similar, with 94% to 100% of both groups above protective levels (>/=1:8). The difference in GMT values of polio serotype 3 approached significance (29 vs 73); fewer preterm children had protective titer values (75% vs 100%). Among children vaccinated against hepatitis B, 75% of preterm and 71% of full-term children were protected (10 mIU/mL). Preterm children immunized at the recommended chronological ages displayed antibody responses similar to those for full-term children for most immunizing antigens. Responses to PRP and polio serotype 3 were less robust than those of full-term children.

The Immunogenicity of Haemophilus influenzae Type B Conjugate Vaccines in Children Born to HIV-Infected Women † 899

Although immunocompromise due to HIV-1 (HIV) infection increases the importance of receipt of routine childhood vaccines, such vaccines appear to have decreased immunogenicity in these children. The study's objectives were to evaluate the immunogenicity of Haemophilus influenzae type B(Hib) conjugate vaccines among HIV-infected children according to clinical and immunologic disease progression as well as viral load. The concentration of antibody to polyribosylribitolphosphate (PRP) was measured at approximately nine and 24 months of age in plasma specimens from children of HIV-infected women enrolled in the Women and Infants Transmission Study. Of 227 children at the 9-month visit known to have received age-appropriate immunization with a Hib conjugate vaccine, the geometric mean antibody concentration (GMAC) was lower among 35 HIV-infected children (1.64 μg/ml) as compared to uninfected children (2.70 μg/ml), although the difference was not statistically significant. The proportion of children with antibody concentrations ≥ 1.0μg/ml did not differ significantly according to HIV infection status (73% uninfected, 74% infected). Neither the GMAC nor the proportion of children with antibody concentrations ≥ 1.0 μg/ml varied significantly among these HIV-infected children with predominantly mild-moderate disease progression according to clinical category, immunologic stage, or viral load(p ≥ 0.37). Similar results were obtained among 127 children (17 HIV-infected) eligible for analysis at the 24-month study visit. Changes in antibody concentrations over time did not differ significantly among HIV-infected as compared to uninfected children (p = 0.87). These results suggest that HIV-infected children with mild-moderate disease progression may have an adequate quantitative antibody response to Hib conjugate vaccines during the first two years of life. Additional investigations of the immune response to Hib conjugate vaccines, including the qualitative antibody response to immunization, should be pursued.

A Simple and Rapid Method for Measuring Unconjugated Capsular Polysaccharide (PRP) ofHaemophilus influenzaetype b in PRP-tetanus toxoid conjugate vaccine

The authors developed a simple rapid method for quantitation of free capsular polysaccharide ofHaemophilus influenzaetype b (polyribosyl ribitol phosphate, PRP) in PRP-tetanus toxoid conjugate vaccine based on acid precipitation of tetanus toxoid (TT). Acid hydrolysis of PRP during the assay was not detected. The conditions used in the assay did not precipitate unconjugated PRP or adipic acid dihydrazide derivatized PRP. The method was highly reliable, reproducible and sensitive. The accuracy of the assay was confirmed by spiking known amounts of unconjugated PRP to PRP-TT conjugate preparations. A PRP-TT preparation, incubated at 37°C for 6 months showing most of the PRP as unconjugated (87% determined by this method), was not immunogenic in mice for the PRP component even after two injections. In contrast, the same preparation held at 4°C for 20 months, showing 17% unconjugated PRP, induced IgG antibodies to PRP which were boosted after second injection. Therefore, this method is very useful to evaluate the stability of PRP-TT conjugate vaccine. The assay may be useful for characterizing other polysaccharide-protein conjugate vaccines.

Randomised controlled trial of combined diphtheria, tetanus, whole-cell pertussis vaccine administered in the same syringe and separately with Haemophilus influenzae type b vaccine at two, three and four months of age

An open randomised controlled multicentre study compared the immunogenicity and reactogenicity of three vaccines given by injection at two, three and four months of age. Children (89) received Haemophilus influenzae type b (Hib) vaccine (SmithKline Beecham Biologicals [SB]) administered in the same syringe with combined diphtheria–tetanus–whole-cell pertussis (DTP W) vaccine (Evans); 75 received Hib vaccine (SB) administered as a separate injection with DTP W vaccine; 66 received Hib vaccine (Pasteur Merieux [PM]) administered as a separate injection with DTP W vaccine. All subjects in both groups receiving Hib (SB) vaccine had levels of antibodies to the Hib polysaccharide polyribosylribitol phosphate (PRP) greater than 0.15 μg ml −1 as did 97% of those receiving Hib (PM) vaccine 1 month after administration of the final vaccine dose. Subjects in all three groups demonstrated an immunological response to pertussis, diphtheria and tetanus antigens. The geometric mean titres of the group given Hib (SB) and DTP W vaccine mixed in the same syringe were lower than the other groups. There were no apparent differences between the treatment groups in the incidence of local or systemic reactions, or serious adverse events. This study has confirmed that it is possible to halve the number of injections necessary to offer protection, with advantages to parents, children, doctors and nurses, using a combined DTP WHib vaccine and in accordance with the UK's accelerated primary immunisation schedule at two, three and four months of age.

The acylated form of protein D of Haemophilus influenzae is more immunogenic than the nonacylated form and elicits an adjuvant effect when it is used as a carrier conjugated to polyribosyl ribitol phosphate.

The nonacylated form of protein D (PDm) of Haemophilus influenzae has been shown to induce the production of antibodies that are bactericidal to homologous and heterologous nontypeable H. influenzae (NTHi) strains. In this study, immunization of rats with lipoprotein D (LPD) induced higher levels of anti-protein D immunoglobulin G and A serum antibodies than immunization with PDm, and the bactericidal activities of sera from LPD-immunized rats were greater than those of sera from PDm-immunized rats. Immunization with LPD or PDm did not prevent the development of acute otitis media (AOM) when rats were challenged with 10(4) CFU of an NTHi strain. However, on the eighth day of bacterial challenge, 50% (5 of 10) of LPD-immunized rats had recovered from otitis media and 30% (3 of 10) had negative middle ear cultures, whereas only 30% (3 of 10) of PDm-immunized rats had recovered, though none was culture positive. Immunization with an inactivated homologous bacterial strain elicited 70% protection (i.e., 7 of 10 rats) in the rat otitis media model. LPD and PDm were also conjugated to the H. influenzae type b (Hib) capsular polysaccharide, polyribosyl ribitol phosphate (PRP), to test protein D-conjugated PRP vaccine's potential for protection against Hib infection. When two LPD-conjugated and two PDm-conjugated PRP vaccines, each containing a different protein concentration, and a tetanus toxoid-conjugated vaccine (ACT-HIB) were tested in the experimental model of rat otitis induced with a Hib strain (Minn A), both of the LPD-conjugated and one of the PDm-conjugated vaccines induced significant protection from AOM, the level of protection being highest in animals given the vaccine with the highest LPD content. Sera from these rats also manifested the highest anti-PRP and anti-LPD antibody levels and the highest bactericidal activities against a Hib strain and an NTHi strain.

Administration of Combined Diphtheria and Tetanus Toxoids and Pertussis Vaccine, Hepatitis B Vaccine, andHaemophilus influenzaeType b (Hib) Vaccine to Infants and Response to a Booster Dose of Hib Conjugate Vaccine

We compared antibody levels following separate but simultaneous administration of diphtheria and tetanus toxoids with acellular pertussis vaccine (DTaP) containing pertussis toxoid, filamentous hemagglutinin, and pertactin (PRN); hepatitis B vaccine; and Haemophilus influenzae type b polysaccharide (polyribosylribitol phosphate; PRP) vaccine conjugated to tetanus toxoid (PRP-T) with those following administration of a combination of a DTaP-hepatitis B vaccine-PRP-T to infants at 2, 4, and 6 months of age. The antibody response to a booster dose of PRP conjugate vaccine (CRM197-OS) in infants with low (< 1 microgram/mL) or undetectable (< 0.10 microgram/mL) postpriming levels of antibody to PRP was also studied. Antibody levels were quantitated before and after dose 3 by enzyme-linked immunosorbent assay, radioimmunoassay, or neutralization assay. Seroresponse rates were not different between the two vaccine groups except for rates of response to PRP. There was a trend that levels of antibody to all the antigens included in the combination vaccine were lower than those of antibody to antigens in separate vaccines; for levels of antibody to diphtheria toxoid (P = .001), PRN (P < .0001), and PRP (P < .0001), the differences were significant. Despite low or undetectable postpriming levels of antibody to PRP, high-titered (geometric mean concentration, 9.02 micrograms/mL; range, 1.0-81.5 micrograms/mL), immunoglobulin G-predominant antibody to PRP was produced following a booster dose of CRM197-OS, a finding consistent with a memory response.

The baboon as a nonhuman primate model for assessing the effects of maternal immunization with Haemophilus influenzae type b polysaccharide vaccines.

These studies were performed to assess the utility of the baboon as a nonhuman primate model to evaluate vaccines for use in humans. Specifically, we examined the antibody response of baboons immunized during the third trimester of pregnancy with Haemophilus influenzae type b (Hib) polyribosylribitol phosphate (PRP) conjugate and unconjugated polysaccharide vaccines. Some of the vaccinated mothers failed to respond to a single immunization with unconjugated Hib PRP. Specific Hib PRP immunoglobulin G (IgG) but not IgM antibodies cross the baboon placenta and are detected in the offspring. Higher-titer baboon anti-Hib PRP did not express two previously defined cross-reactive human anti-Hib PRP idiotypes and was biased towards lambda light-chain expression. Spectrotype analysis indicated that baboon anti-Hib PRP was restricted in heterogeneity and oligoclonal.

Immunity to Haemophilus influenzae type b after reimmunization with oligosaccharide CRM197 conjugate vaccine in children with human immunodeficiency virus infection.

Immunity to Haemophilus influenzae type b after reimmunization with oligosaccharide CRM197 conjugate vaccine in children with human immunodeficiency virus infection.

Interchangeability of Haemophilus influenzae Type b vaccines in the Primary Series: Evaluation of a Two-dose Mixed Regimen

To evaluate two- or three-dose "mixed" regimens of Haemophilus influenzae type b conjugate vaccines in the priming series. Two randomized clinical trials with 140 and 181 infants, respectively. Private practices in New Orleans and Chicago. In trial I, infants received one of four regimens. Two were recommended regimens for polyribosylribitol phosphate (PRP)-meningococcal protein conjugate (M) and PRP-tetanus toxoid conjugate (T). Two mixed regimens consisted of M at 2 months followed by two doses of T or PRP-diphtheria toxoid conjugate (D) at 4 and 6 months. Trial II consisted of three groups. Two were recommended regimens for M and T. The third was a two-dose mixed regimen consisting of M at 2 months and T at 4 months. Parents were interviewed and instructed to record side effects after each vaccination. Serum was assayed for H influenzae type b anticapsular antibody (anti-PRP). Minor differences in safety profiles likely reflected alpha error. In trial I, M (lot 0884T, one of several known to have had decreased immunogenicity), probably primed for substantial increase in serum antibody when D or T was given at 4 and 6 months. In trial II, infants who received the two-dose mixed regimen (M from immunogenic lot 0116W at 2 months and T at 4 months) had a significantly higher mean area under the curve than recipients of the three-dose TTT regimen when antibody concentration was plotted against age, although the geometric mean anti-PRP antibody concentration for the MT-recipients was significantly lower at 7 months. M used in trial I may have primed infants despite poor immunogenicity. The two-dose mixed regimen (MT-) in trial II produced a mean anti-PRP antibody concentration with higher sustained anti-PRP concentrations from 2 to 7 months, as judged by the area under the curve, but a lower mean anti-PRP antibody concentration at 7 months.