Pneumococcal Polysaccharide-protein Conjugate Vaccine Research Articles

Impact of aluminum adjuvants on the stability of pneumococcal polysaccharide-protein conjugate vaccines

Development of a vaccine drug product requires formulation optimization to ensure that the vaccine’s effectiveness is preserved upon storage throughout the shelf-life of the product. Although aluminum adjuvants have been widely used in vaccine formulations to safely and effectively potentiate an immune response, careful attention must be directed towards ensuring that the type of aluminum adjuvant does not impact the stability of the antigenic composition. PCV15 is a polysaccharide-protein conjugate vaccine comprising the pneumococcal polysaccharide (PnPs) serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F and 33F), each individually conjugated to the protein carrier CRM197. PCV15 was formulated with either amorphous aluminum hydroxyphosphate sulfate adjuvant (AAHS) or aluminum phosphate adjuvant (AP) and examined for both stability and immunogenicity. Using a collection of methods to evaluate vaccine stability, it was discovered that certain PCV15 serotypes (e.g., 6A, 19A, 19F) formulated with AAHS resulted in a reduction of immunogenicity in vivo and a reduction in recoverable dose as tested by an in vitro potency assay. The same polysaccharide-protein conjugates formulated with AP were stable regarding all measures tested. Moreover, the reduction in potency of certain serotypes correlated with chemical degradation of the polysaccharide antigen caused by the aluminum adjuvant as measured by reducing polyacrylamide gel electrophoresis (SDS-PAGE), High-Pressure Size Exclusion Chromatography coupled with UV detection (HPSEC-UV) and ELISA immunoassay. This study suggests a formulation, which includes AAHS, may negatively impact the stability of a pneumococcal polysaccharide-protein conjugate vaccine that contains phosphodiester groups. This decrease in stability would likely result in a decrease in the “active” concentration of antigen dose, and herein, it is shown that such instability directly compromised vaccine immunogenicity in an animal model. The results presented in this study help to explain critical degradation mechanisms of pneumococcal polysaccharide-protein conjugate vaccines.

An affordable pneumococcal conjugate vaccine after 20 years

An affordable pneumococcal conjugate vaccine after 20 years

Effect of HIV-exposure and timing of antiretroviral treatment initiation in children living with HIV on antibody persistence and memory responses to Haemophilus influenzae type b and pneumococcal polysaccharide-protein conjugate vaccines

BackgroundWe investigated the effect of in utero HIV-exposure, timing of antiretroviral treatment (ART) initiation, and ART interruption on memory responses and persistence of immunity induced by pneumococcal (PCV) and Haemophilus influenzae type b (HibCV) polysaccharide-protein conjugate vaccines. MethodsChildren were enrolled (6–12 weeks of age), and vaccinated with a three-dose primary series of 7-valent PCV (PCV7) and HibCV at 6, 10 and 14 weeks of age. Study groups included infants infected with HIV perinatally with CD4+ ≥ 25% initiating ART following immunological or clinical deterioration (ART-Def), or immediately upon enrolment followed by interruption at 40 (ART-Immed/40w) or 96 weeks (ART-Immed/96w); and HIV-uninfected infants with (HEU), and without HIV (HIV-unexpsoed) exposure in utero. Within each group, children were randomized to receive either a booster dose of PCV7 or HibCV at 15 months of age. PCV serotype-specific and polyribosyl ribitol phosphate (PRP) IgG were measured pre-boost, two-weeks post-boost and at two-years of age. Opsonophagocytic activity (OPA) to serotypes 9V, 19F and 23F was measured post-booster dose. ResultsPersistence of IgG to PCV vaccine–serotypes and anti-PRP was similar in all groups of children living with HIV (CLWH) compared to HIV-unexposed children. Anamnestic responses to PCV and HibCV were also similar in all three groups of CLWH compared to HIV-unexposed children. CLWH, however, tended to have lower functional antibody (OPA) titers than HIV-unexposed children after the PCV booster dose for some serotypes. Immunity to PCV and HibCV was similar between the ART-Immed/40w and ART-Immed-96w groups. There were no differences in IgG kinetics between HEU and HIV-unexposed children. ConclusionsA three dose primary series, with or without PCV or HibCV booster doses in CLWH initiated on ART during infancy, would likely be similarly effective in preventing invasive bacterial disease as in HIV-unexposed children.

Persistence of Pneumococcal Antibodies After Primary Immunisation With a Polysaccharide–Protein Conjugate Vaccine

P Zimmerman, KP Perrett, G Berbers, N Curtis. Arch Dis Child. 2019;104(7):680–684 The pneumococcal polysaccharide-protein conjugate vaccine (PCV) is a part of the primary vaccination series recommended by the World Health Organization (WHO) as well as the Centers for Disease Control and Prevention (CDC). The purpose of this study was to examine the protective antibody response at 7 and 13 months to PCV by following the primary vaccination series recommended by the WHO, using the 3 + 0 schedule (PCV at 6 weeks, 3–4 months, and 4–6 months of age). Patients were gathered from a previous patient population that was a part of the Melbourne Infant Study: BCG for Allergy and Infection Reduction that was looking at BCG immunization at birth and the protective nature against allergy, childhood infection, and asthma from whom blood samples were collected at 7 and/or 13 months of age. All of these infants were in Melbourne, Australia, and were a part of the Australian National Immunization program from 2013 to 2016. Inclusion criteria were infants born at >32 weeks’ gestation, birth weight >1500 g, mother who was …

Impact of HIV-1 infection and antigen class on T follicular helper (TFH) cell responses to pneumococcal polysaccharide-protein conjugate vaccine (PCV-13)

Abstract Pneumococcal infections are common and serious complications of HIV-1 disease. Prevention has been compromised by the limited magnitude and quality of antibody responses to T cell-independent (TI-2) pneumococcal capsular polysaccharides (PPS). The PCV-13 vaccine conjugates PPS to a T cell-dependent (TD) protein (diphtheria toxoid; DT). We investigated the differential response to PPS and DT by antibody-secreting B cells (ASC) after immunization with PCV-13 in newly-diagnosed healthy HIV+ and control adults. The numbers of PPS-specific IgG ASC increased significantly and similarly in HIV+ and controls 1 week after vaccination. However, DT-specific IgG ASC increased significantly in controls but not HIV+ subjects. To determine the cellular basis of these disparate responses to DT and PPS, we characterized the frequency and activation of T follicular helper (TFH) cells, the predominant T cell subset providing B cell help. The percentages of and intracellular IL-21 in TFH cells were unchanged with vaccination. However, expression of ICOS, which sustains TFH function and phenotype, increased significantly after vaccination among controls, but not the HIV+ group. Increases in ICOS+ TFH correlated with changes in TD DT-specific IgG ASC in controls but not in HIV+. In contrast, ICOS expression did not correlate with TI-2 PPS-specific ASC in either group. Levels of TFH differentiating factors IL-12 and IL-6 increased post vaccination only in controls. In summary, although TI-2 PPS-specific responses were similar in both groups and independent of TFH activation, TFH ICOS-expression was most closely related to responses to TD DT, which were compromised even in recently diagnosed healthy HIV+ adults.

Cost-Effectiveness of a 10- Versus 13-Valent Pneumococcal Conjugate Vaccine in Denmark and Sweden

BackgroundThe introduction of a 7-valent pneumococcal polysaccharide-protein conjugate vaccine (PCV7) had profound public health effects across the globe. PCV7 vaccination in a national immunization program is generally considered cost-effective and potentially cost-saving. Two new PCVs have been launched, a 10-valent pneumococcal conjugate vaccine (PCV10) and a 13-valent pneumococcal conjugate vaccine (PCV13). ObjectiveThis article examines the public health and economic effects of pediatric national immunization programs of PCV10 and PCV13 in Denmark and Sweden. MethodsA previously published decision-analytic model was used to estimate the impact of PCV10 and PCV13 on reducing cases of invasive pneumococcal disease (IPD), pneumonia (PNE), and acute otitis media (AOM) by using country-specific incidence, serotype coverage, disease sequelae, mortality, vaccine effectiveness, indirect effects, costs, and utilities. Direct effects for PCV13- and PCV10-covered serotypes were assumed similar to PCV7. PCV13 was assumed to confer an indirect effect, similar to PCV7, whereas PCV10 was not. Assumptions were tested in sensitivity analyses. ResultsPCV13 is expected to save 280.7 million DKK (Danish kroner) in Denmark and 288.2 million SEK (Swedish kronor) in Sweden in direct costs compared with a vaccination program with PCV10. In both Denmark and Sweden, the results of this study indicate that, compared with PCV10, PCV13 will have a greater impact on disease in life-years gained (LYG), quality-adjusted life-years (QALYs) gained, IPD cases avoided, PNE cases avoided, AOM cases avoided, and in deaths avoided. For Denmark PCV13, it was estimated to result in 10,051 LYG; 9063 QALYs gained; 237 additional IPD cases avoided; 12,094 additional PNE cases avoided; 958 additional cases of AOM avoided; and 882 additional deaths avoided. For Sweden PCV13, it was estimated to result in 4245 LYG; 3953 QALYs gained; 379 additional IPD cases avoided; 8210 additional PNE cases avoided; 1459 additional cases of AOM avoided; and 378 additional deaths avoided. In all sensitivity analyses, PCV13 was less costly and more effective compared with PCV10. ConclusionsIn this analysis, a national immunization program with PCV13 was found to be good value for money and estimated to prevent additional cases of disease among children and nonvaccinated individuals and save additional costs due to treatment of pneumococcal disease, when compared with PCV10 in Denmark and Sweden.

Respiratory viral and pneumococcal coinfection of the respiratory tract: implications of pneumococcal vaccination

The interactions between Streptococcus pneumoniae and other respiratory pathogens have been studied in vitro, in animal models and in humans – including epidemiologic and vaccine probe studies. Interactions of pneumococcus with respiratory viruses are common, and many mechanisms have been suggested to explain this phenomenon. The aim of this review is to explore pneumococcal interactions with respiratory viruses and consider the potential role that the pneumococcal polysaccharide–protein conjugate vaccine may play in modifying pneumococcal–respiratory viral interactions.

Immunologic responses to polysaccharides and polysaccharide–conjugate vaccines are complex

The concurrent evaluations of pneumococcal nasopharyngeal colonization and responsiveness to pneumococcal polysaccharide-protein conjugate vaccine (PCV) provide insight into the complexity of immunologic responses. We knew that PCV affects colonization, and now we know that colonization affects PCV response. In the current study from the Netherlands, investigators found a dampening effect of carrying or having carried S pneumoniae in the nasopharynx on type-specific antibody response to PCV at 24 months of age. This phenomenon has been reported for young infants, particularly for those who had type-specific colonization prior to their first dose of PCV. Exhaustion of B lymphocytes (presumably “busy” reacting to colonizing strains) in immunologically immature infants was proposed as the mechanism of hyporesponsiveness. Finding the same dampening effect in 24-month old (presumably more immunologically mature) previously immunized/not previously immunized children who were found to be recently colonized with S penumoniae vaccine serotypes helps to clarify what seems to be complex and multifaceted bacterial polysaccharide–protein conjugate–host interactions. Clinical importance of diminished antibody response in the context of nasopharyngeal colonization is unknown. Article page 965▶ Lower Immunoglobulin G Antibody Responses to Pneumococcal Conjugate Vaccination at the Age of 2 Years after Previous Nasopharyngeal Carriage of Streptococcus pneumoniaeThe Journal of PediatricsVol. 159Issue 6PreviewTo determine whether nasopharyngeal pneumococcal carriage with serotypes 6B, 19F, or 23F interferes with immunoglobulin G (IgG) antibody responses to vaccination with 7-valent pneumococcal conjugate vaccine (PCV7) at the age 24 months. Full-Text PDF

Review on the immunogenicity and safety of PCV-13 in infants and toddlers

Pneumococcal polysaccharide–protein conjugate vaccines (PCVs) generally protect against vaccine-serotype-specific pneumococcal disease. Additional serotypes included in the new 13-valent PCV (PCV-13) formulation and not in the first-generation 7-valent PCV (PCV-7) formulations are 1, 3, 5, 6A, 7F and 19A. Importantly, serotype 1 is associated with a high proportion and burden of pneumococcal disease in low-income countries, whilst serotype 19A emerged as the dominant disease-causing serotype following widespread PCV-7 immunization in the USA. In this article we present the available data on the immunogenicity and safety of PCV-13 in infants and children. Noninferiority studies indicate a similar immunogenicity profile between PCV-13 and PCV-7 recipients against most of the common serotypes. A favorable immunogenicity profile was also observed for at least five of the additional serotypes in PCV-13. An attenuated anamnestic response to serotype 3 was reported in five out of 14 studies. PCV-13 was demonstrated to have a similar acceptable safety profile to PCV-7 and no interference in immunogenicity of other concomitantly administered childhood vaccines was observed among PCV-13 recipients.

Impact of conjugate pneumococcal vaccines on the changing epidemiology of pneumococcal infections

Streptococcus pneumoniae-related infections have a major global impact on healthcare, especially in the developing world, and are considered the number one vaccine-preventable cause of death in children. There are more than 90 pneumococcal serotypes and 46 serogroups. The first capsular polysaccharide pneumococcal vaccine was licensed in the USA in 1977 for individuals older than 2 years of age at high risk for pneumococcal disease. Two decades later, the first 7-valent pneumococcal polysaccharide–protein conjugate vaccine completed the required clinical trials and was introduced as part of the national immunization program of various countries. New-generation vaccines that include emerging serotypes, while maintaining protection against the 7-valent pneumococcal serotypes, have recently been approved. With the addition of these serotypes, the majority of potential pneumococcal serotypes causing invasive disease in most parts of the world could be covered.

Role of Streptococcus pneumoniae in Hospitalization for Acute Community-acquired Pneumonia Associated With Culture-confirmed Mycobacterium tuberculosis in Children

African children hospitalized with symptoms of severe acute pneumonia, which resolves following empiric antibiotic therapy, are sometimes identified to have underlying culture-confirmed pulmonary tuberculosis (PTB). Experimental studies suggest Mycobacterium tuberculosis infection predisposes to Streptococcus pneumoniae infection; however, diagnostic limitations make it difficult to quantify this association in children. We aimed to probe the extent of pneumococcal coinfection in children with PTB, using a vaccine-probe design study. A post hoc analysis of PTB cases occurring among 39,836 participants in a phase III randomized, double-blind placebo-controlled 9-valent pneumococcal polysaccharide-protein conjugate vaccine (PCV9) trial in South Africa was undertaken. Hospitalization for PTB occurring during the 5.3 years of follow-up were identified and categorized as culture-confirmed PTB or probable/possible-PTB. The incidence rates of hospitalized PTB were compared between PCV9 vaccinees and placebo recipients. Hospitalization for culture-confirmed PTB was 43.4% (95% CI, 9.7%–65.1%) less likely among vaccinees (n = 30) compared with placebo recipients (n = 53), incidence, 20 versus 35 per 100,000 child-years of follow-up (P = 0.0117). In HIV-infected children, culture-confirmed PTB was 47.3% (95% CI, 8.6%–69.6%) less likely among vaccinees (n = 19) compared with placebo recipients (n = 36), P = 0.0203. The incidence of possible/probable PTB did not differ by vaccination status. This vaccine-probe design study suggests that in a setting with high HIV and TB prevalence, culture-confirmed PTB in African children, which frequently presents with symptoms of acute pneumonia, is probably associated with superimposed pneumococcal pneumonia. Children admitted with pneumonia in these settings should be investigated for underlying PTB.

CDC Issues Recommendations for a New Pneumococcal Conjugate Vaccine

Target Population: Infectious diseases specialists, as well as physicians, nurses, and public health workers who care for children Sponsoring Organization: CDC Type: Recommendations of the Advisory Committee on Immunization Practices. This report is consistent with recommendations by the American Academy of Pediatrics Committee on Infectious Diseases. Key Points: In February 2000, a 7-valent pneumococcal polysaccharide-protein conjugate vaccine (Prevnar [PCV7]) was licensed for infants and young children in the U.S. Subsequently, the rates of pneumococcal sepsis and meningitis in children fell, but infections caused by nonvaccine serotypes have persisted, and the prevalence of nonvaccine serotypes may be increasing. On February 24, 2010, a 13-valent pneumococcal polysaccharide-protein conjugate vaccine …

Safety profile of pneumococcal conjugate vaccines: systematic review of pre-and post-licensure data

A 7-valent pneumococcal polysaccharide-protein conjugate vaccine (PCV7) was licensed in the United States of America in 2000, but no comprehensive postmarketing review of safety has been carried out. We conducted a systematic review of the safety of PCV7 and other pneumococcal conjugate vaccines. A total of 42 studies were included in the review. Reactogenicity data from some randomized trials suggest that PCV7 may result in more local reactions and fever than certain comparison vaccines. However, the reactions were mild and self-limited, and PCV7 did not carry an increased risk of severe injection-site reactions or high fever. Some, although not all, of the randomized trials in children found that mild local and systemic reactions associated with PCV7 may increase with the number of doses, at least over the three-dose primary series. In addition, PCV7 and other pneumococcal conjugate vaccines were found to have tolerable reactogenicity in Native American and African populations and in medically high-risk groups for which pneumococcal vaccination is recommended. Two of the largest studies of PCVs, one involving PCV7 and the other, PCV9, found a statistically significant increased risk of hospitalization for reactive airway disease, including asthma. Another large trial of PCV9, however, did not find an increased risk of asthma. In conclusion, this review of the evidence did not identify any major safety problems with PCV7 or any other pneumococcal conjugate vaccine, with the possible exception of reactive airway disease, which may bear further scrutiny as additional data become available.

The impact of indirect (herd) protection on the cost-effectiveness of pneumococcal conjugate vaccine

Background: The heptavalent pneumococcal polysaccharide-protein conjugate vaccine (PCV7) confers protection against invasive pneumococcal disease (IPD) caused by serotypes that are responsible for substantial morbidity and mortality throughout the world. In 2000, the 7 serotypes covered by PCV7 accounted for 80% to 90% of serotypes isolated from the blood or cerebrospinal fluid of children aged <6 years in the United States. A previous review of the literature spanning the years 1998 to 2005 pertaining to the incidence of IPD among nonimmunized individuals in countries with universal PCV7 immunization suggested an indirect protective effect (herd protection, or community immunity) after widespread vaccination. Consideration of indirect protection against IPD may enhance cost-benefit evaluations of vaccination programs.Objective: The objective of this analysis was to review the literature on cost-effectiveness analyses of PCV7 vaccination to determine whether inclusion of the indirect effect in decision-analysis models substantially affects the cost-effectiveness findings in favor of vaccination.Methods: A literature review of cost-effectiveness analyses of PCV7 vaccination was conducted using the DIMDI (Deutschen Institut fur Medizinische Dokumentation und Information) superbase, which comprises 12 databases, to identify articles published between January 2000 and October 2006 using the search terms 7-valent pneumococcal conjugate vaccine AND herd immunity/herd effect, and 7-valent pneumococcal conjugate vaccine AND cost-effectiveness, cost-utility, or cost-benefit analyses. Monetary values were converted to euros and inflated to 2006 values, and events avoided were converted to rates per 100,000 vaccinated to allow comparison across studies. The sensitivity analyses from the models that included indirect effects were examined.Results: There was wide variability in the health-economic results of the 16 studies that met the inclusion criteria. In studies that did not include indirect effects, the adjusted cost per life-year gained ranged from cost saving to €140,723 from the societal perspective and from €56,724 to €324,218 from the payer perspective. In the 4 studies that included indirect effects, a significant and consistent improvement was seen in the health-economic results in favor of vaccination with PCV7. No trends in variability across time or geographic region were observed.Conclusions: Indirect effects had a significant effect on cost-effectiveness, as seen in the sensitivity analyses. Future models should include indirect effects in evaluating the cost-effectiveness of PCV7.

Maternal Pneumococcal Conjugate Immunization Protects Infant Chinchillas in the Pneumococcal Otitis Media Model

Infant immunization with pneumococcal polysaccharide-protein conjugate vaccines (PCVs) is unlikely to elicit protective serum antibody concentrations during the first 4-6 months of life, when recurrent pneumococcal otitis media (POM) often begins. We therefore investigated a maternal pneumococcal immunization strategy to prevent early infant POM. Pregnant chinchillas (dams) received injections of heptavalent PCV or saline. Post-partum maternal and infant (kits) blood samples were obtained, and kits were subsequently challenged by intranasal inoculation of a vaccine-type pneumococcal strain (19F). Anti-pneumococcal capsular polysaccharide IgG antibody (Ab) concentration was measured using an ELISA in maternal and kit serum samples. Immunized dams and their kits had significantly higher Ab titers than control dams and their kits. Antibody titer in kits declined with a half-life of 12 days. Maternal immunization significantly reduced both the incidence ( p = 0.05) and severity ( p < 0.01) of experimental POM in chinchilla kits, and was 82% effective at preventing mortality from invasive pneumococcal disease. Pre-challenge serum Ab concentration in kits was the single best predictor of POM severity ( r = -0.66). This experiment strongly supports the hypothesis that maternal immunization with PCV will reduce the burden of early infant POM and invasive pneumococcal disease.

Pneumococcal Conjugate Vaccine

In February 2000, the new 7-valent pneumococcal polysaccharide-protein conjugate vaccine (PCV7) (Prevnar; Wyeth Lederle Vaccines, Pearl River, NY) was approved by the Food and Drug Administration (FDA) for the prevention of invasive pneumococcal disease (eg, meningitis and bacteremia) in infants and young children. This long-awaited event has received widespread applause from pediatric infectious disease experts who anticipate a dramatic decrease in these potentially fatal serious infections as the infants and young children who are at high risk become immunized. 1,2 The Centers for Disease Control and Prevention Advisory Committee on Immunization Practices (ACIP) recommends that the vaccine be given to all infants aged 2 to 23 months and to children aged 24 to 59 months who are at increased risk for pneumococcal disease, such as those who have sickle cell disease, human immunodeficiency disease virus infection, and other immunocompromising or chronic medical conditions.3 The ACIP also recommends that the vaccine be considered for all other children aged 24 to 59 months, with priority given to (1) those who are 24 to 35 months old; (2) those who are of Alaska Native, American Indian, or African American descent; and (3) those who attend group day care centers. Even though the vaccine has been demonstrated to be safe and effective in preventing invasive pneumococcal infections, the prevention of otitis media is another potential advantage. However, there is uncertainty among clinicians as to the impact this vaccine will have in preventing pneumococcal otitis media; thus, we otolaryngologists should be knowledgeable when we counsel parents and caregivers of infants and children who have acute otitis media (AOM) on what to realistically expect from the immunization.

Serum opsonic activity in infants with sickle-cell disease immunized with pneumococcal polysaccharide protein conjugate vaccine. The Pneumococcal Conjugate Vaccine Study Group.

Pneumococcal infections are an important cause of morbidity and mortality in children with sickle-cell disease (SCD). Pneumococcal conjugate vaccines (PCVs) are immunogenic in healthy infants <2 years of age but have not been evaluated in young children with SCD. Infants with SCD were immunized with a 7-valent PCV (Wyeth-Lederle Vaccines & Pediatrics) at 2, 4, and 6 months of age. A booster dose of 23-valent pneumococcal polysaccharide vaccine (PPV; Pnu-Immune) was administered at 24 months of age. Antipneumococcal type 6B and 14 serum opsonic activity was measured to assess the biologic function of the antibody. Following the administration of three doses of PCV, opsonic activity against serotype 6B increased from 4. 8% at 2 months to 33.5% at 7 months, with a subsequent decline to 8.1% at 12 months and 7.5% at 24 months and with an increase to 30.7% at 25 months after administration of a booster dose of PPV. Similar trends were seen with serotype 14 (opsonic activities were 9.4% at 2 months, 24.9% at 7 months, 16.5% at 12 months, and 12.6% at 24 months, and the opsonic activity was 27.3% 1 month after the administration of PPV). Serum opsonic activity correlated with antibody levels for both serotypes. PCV induces serum opsonic activity in infants with SCD. Antipneumococcal serum opsonic activity correlates with antibody levels.

CpG oligodeoxynucleotides act as adjuvants for pneumococcal polysaccharide-protein conjugate vaccines and enhance antipolysaccharide immunoglobulin G2a (IgG2a) and IgG3 antibodies.

Pneumococcal polysaccharide-protein conjugate vaccines elicit antipolysaccharide antibodies, but multiple doses are required to achieve protective antibody levels in children. In addition, the immunogenicity of experimental multivalent pneumococcal conjugate vaccines varies with different polysaccharide serotypes. One strategy to improve these vaccines is to incorporate an adjuvant to enhance their immunogenicity. Synthetic oligodeoxynucleotides containing unmethylated CpG motifs (CpG ODN) are adjuvants that promote T-cell and T-dependent antibody responses to protein antigens, but it has been unclear whether CpG ODN can enhance polysaccharide-specific antibody responses. The present studies demonstrate significant adjuvant activity of CpG ODN for antibody responses against Streptococcus pneumoniae polysaccharide types 19F and 6B induced by conjugates of 19F and 6B with the protein carrier CRM(197). BALB/c ByJ mice were injected with 19F-CRM(197) or 6B-CRM(197) with or without CpG ODN, and sera were tested for anti-19F or anti-6B antibodies by enzyme-linked immunosorbent assay. The polysaccharide-specific antibody response to 19F-CRM(197) alone was predominantly of the immunoglobulin G1 (IgG1) and IgM isotypes, but addition of CpG ODN markedly increased geometric mean titers of total anti-19F antibody (23-fold), anti-19F IgG2a (26-fold), and anti-19F IgG3 (>246-fold). The polysaccharide-specific antibody response to 6B-CRM(197) alone consisted only of IgM, but addition of CpG ODN induced high titers of anti-6B IgG1 (>78-fold increase), anti-6B IgG2a (>54-fold increase), and anti-6B IgG3 (>3,162-fold increase). CpG ODN also increased anti-CRM(197) IgG2a and IgG3. Adjuvant effects were not observed with control non-CpG ODN. Thus, CpG ODN significantly enhance antipolysaccharide IgG responses (especially IgG2a and IgG3) induced by these glycoconjugate vaccines.

Circulating antibody secreting cell response to parenteral pneumococcal vaccines as an indicator of a salivary IgA antibody response

This study assessed the mucosal immune response in healthy adult volunteers immunized parenterally with either pneumococcal polysaccharide ( N = 8) or pneumococcal polysaccharide-protein conjugate ( N = 10) vaccine with an aim to evaluate the relevance of antibody secreting cell (ASC) response after parenteral vaccination. An ASC response to the four types of capsular polysaccharide tested was observed in all vaccinees 7–9 days after immunization. IgA was the predominant class in the ASC response, and IgG the next common, with very few IgM ASCs. The IgA IgG ratio in the ASC response was higher after immunization with the polysaccharide than the conjugate vaccine. Antibodies of the IgA class were frequently seen in the saliva already before immunization; especially to serotypes 14 and 19F. A twofold increase of the type specific secretory IgA antibodies in saliva was found in eight of the 16 instances in which the specific IgA ASC response was > 100 ASC per 10 6 cells and in only one of the 52 instances with fewer ASCs. We conclude that the ASC response in the peripheral blood is a useful parameter of the antibody response to pneumococcal vaccines and a good indicator of a secretory IgA response in the saliva.

IMMUNOGENICITY OF A PNEUMOCOCCAL PROTEIN CONJUGATE VACCINE IN INFANTS WITH SICKLE CELL DISEASE. ▴ 946

Pneumococcal infections are an important cause of morbidity/mortality in children with sickle cell disease (SCD). Pneumococcal conjugate vaccines linked to protein carriers are immunogenic in healthy infants < 2 yrs of age, but have not been evaluated in children with SCD. Infants with SCD were immunized with a 7-valent pneumococcal polysaccharide-protein conjugate vaccine (CRM; cross-reacting diphtheria mutant) at 2, 4, and 6 mos. Type specific antibodies were measured by ELISA after pre-absorption with C-polysaccharide. No side effects have been observed. This vaccine appears to be safe and immunogenic, and should provide protection against pneumococcal infections in infants with SCD. (Funded in part by Lederle-Praxis Biologicals.) Table