Pertussis in adults: introduction.
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Adult↗
Biomedical subjects
J B Robbins
Publications and source records attributed to J B Robbins.
Serum IgG antibody responses to pertussis toxin and filamentous hemagglutinin in nonvaccinated and vaccinated children and adults with pertussis.
Levels of IgG antibody to pertussis toxin (PT) and filamentous hemagglutinin (FHA) were measured in paired serum samples from 781 patients fulfilling at least one laboratory criterion for pertussis that was suggested by an ad hoc committee sponsored by the World Health Organization. The patients were participants or family members of participants in a double-blind efficacy trial of a monocomponent pertussis toxoid vaccine. Of 596 nonvaccinated children, 90% had significant (two-fold or more) rises in PT IgG and FHA IgG levels. Only 17 (32%) of 53 children previously vaccinated with three doses of pertussis toxoid had rises in PT IgG levels because they already had elevated PT IgG levels in their acute-phase serum samples. PT IgG and FHA IgG levels were significantly higher in acute-phase serum samples from 29 adults than in acute-phase serum samples from the nonvaccinated children. Nevertheless, significant rises in levels of PT IgG (79% of samples) and FHA IgG (90%) were demonstrated in adults. In conclusion, assay of PT IgG and FHA IgG in paired serum samples is highly sensitive for diagnosing pertussis in nonvaccinated individuals. Assay of PT IgG levels in paired sera is significantly less sensitive for diagnosis of pertussis for children vaccinated with pertussis toxoid.
Adhesins, Bacterial↗
Treatment with succinic anhydride improves the immunogenicity of Shigella flexneri type 2a O-specific polysaccharide-protein conjugates in mice.
Seroepidemiological data and a clinical trial with a Shigella sonnei O-specific polysaccharide (O-SP)-Pseudomonas aeruginosa recombinant exoprotein A (rEPA) conjugate provide evidence that a critical level of immunoglobulin G (IgG) lipopolysaccharide (LPS) antibodies in serum confers protection against shigellosis. We evaluated the immunogenicity of conjugates whose carrier proteins and O-SPs were treated with succinic anhydride (SA), which reacts with amino groups at neutral pH to form amide-linked carboxyls (succinylation). Conjugates were synthesized with either of two genetically inactivated medically useful toxins, the diphtheria protein CRM9 or rEPA, bound to the O-SP of Shigella flexneri type 2a. Conjugates composed of the succinylated protein, succinylated O-SP, or both succinylated components were administered to mice by a clinically relevant scheme, and their levels of serum IgG anti-LPS and anti-proteins were assayed 7 days after the second and third injections. CRM9 served as a more immunogenic carrier than rEPA. Conjugates composed of succinylated components were more immunogenic than the conjugates composed of the native components. SA treatment of both the carrier protein and the O-SP did not confer an advantage over the succinylated protein alone. Conjugates prepared with native proteins, in general, elicited slightly higher levels of IgG protein antibodies than conjugates composed of the SA-treated proteins.
Animals↗
Safety and immunogenicity of Vi conjugate vaccines for typhoid fever in adults, teenagers, and 2- to 4-year-old children in Vietnam.
The capsular polysaccharide of Salmonella typhi, Vi, is an essential virulence factor and a protective vaccine for people older than 5 years. The safety and immunogenicity of two investigational Vi conjugate vaccines were evaluated in adults, 5- to 14-year-old children, and 2- to 4-year-old children in Vietnam. The conjugates were prepared with Pseudomonas aeruginosa recombinant exoprotein A (rEPA) as the carrier, using either N-succinimidyl-3-(2-pyridyldithio)-propionate (SPDP; Vi-rEPA(1)) or adipic acid dihydrazide (ADH; Vi-rEPA(2)) as linkers. None of the recipients experienced a temperature of >38.5 degrees C or significant local reactions. One injection of Vi-rEPA(2) into adults elicited a geometric mean (GM) increase in anti-Vi immunoglobulin G (IgG) from 9.62 enzyme-linked immunosorbent assay units/ml (EU) to 465 EU at 6 weeks; this level fell to 119 EU after 26 weeks. In the 5- to 14-year-old children, anti-Vi IgG levels at 6 weeks elicited by Vi-rEPA(2), Vi-rEPA(1), and Vi were 169, 22.8, and 18.9 EU, respectively (P = 0.0001 for Vi-rEPA(1) and Vi with respect to Vi-rEPA(2)). At 26 weeks, the anti-Vi IgG levels for recipients of Vi-rEPA(2), Vi-rEPA(1), and Vi were 30.0, 10.8, and 13.4 EU, respectively (P < 0.001 for Vi-rEPA(1) and Vi with respect to Vi-rEPA(2)); all were higher than the preinjection levels (P = 0. 0001). Vi-rEPA(2) also elicited the highest anti-Vi IgM and IgA levels of the three vaccines. In the 2- to 4-year-old children at 6 weeks following the first injection, Vi-rEPA(2) elicited an anti-Vi IgG level of 69.9 EU compared to 28.9 EU for Vi-rEPA(1) (P = 0.0001). Reinjection increased Vi antibody levels from 69.9 to 95.4 EU for Vi-rEPA(2) and from 28.9 to 83.0 EU for Vi-rEPA(1). At 26 weeks, anti-Vi IgG levels remained higher than those at preinjection (30.6 versus 0.18 for Vi-rEPA(2) and 12.8 versus 0.33 for Vi-rEPA(1); P = 0.0001 for both). Vi vaccine is recommended for individuals of 5 years of age or older. In the present study, the GM level of anti-Vi IgG elicited by two injections of Vi-rEPA(2) in the 2- to 4-year-old children was higher than that elicited by Vi in the 5- to 14-year-old children (30.6 versus 13.4; P = 0.0001). The safety and immunogenicity of the Vi-rEPA(2) conjugate warrant further investigation.
ADP Ribose Transferases↗
Syntheses and immunologic properties of Escherichia coli O157 O-specific polysaccharide and Shiga toxin 1 B subunit conjugates in mice.
Escherichia coli O157 is the major cause of diarrhea-associated hemolytic uremic syndrome (HUS). Strains causing HUS contain either Shiga toxin 1 (Stx1) or Stx2, or both. In adult volunteers, conjugate vaccines of detoxified lipopolysaccharide (LPS) elicited bactericidal antibodies to E. coli O157. Here, the detoxified LPS was conjugated with improved schemes to the nontoxic B subunit of Stx1. Mice injected with these bivalent conjugates elicited both bactericidal antibodies to E. coli O157 and neutralization antibodies to Stx1.
Animals↗
A mAb recognizing a surface antigen of Mycobacterium tuberculosis enhances host survival.
Murine mAbs reactive with the surface of Mycobacterium tuberculosis were assayed for their ability to affect the course of infection in mice challenged with virulent organisms. An IgG3 mAb (9d8) specific for arabinomannan and reactive with purified antigen from a clinical isolate of M. tuberculosis conferred partial protection on mice after respiratory challenge (30-60% survival >75 days; P </= 0.05). Control mice pretreated with an irrelevant mAb of the same isotype succumbed to tuberculosis within 30 days. Mice with gene disruptions in interferon gamma and major histocompatibility complex Class II also were partially protected from challenge. The protective mAb was neither bactericidal nor inhibitory of infection or bacterial replication. Nevertheless, it profoundly altered the nature of the granulomas in the infected lungs. Mice treated with mAb 9d8 and challenged with M. tuberculosis localized the pathogen within granuloma centers, suggesting that the mAb conferred protection by enhancing a cellular immune response.
Animals↗
On the antigenic determinants of the lipopolysaccharides of Vibrio cholerae O:1, serotypes Ogawa and Inaba.
Monoclonal, murine IgG1s S-20-4, A-20-6, and IgA 2D6, directed against Vibrio cholerae O:1 Ogawa-lipopolysaccharide exhibited the same fine specificities and similar affinities for the synthetic methyl alpha-glycosides of the (oligo)saccharide fragments mimicking the Ogawa O-polysaccharide (O-PS). They did not react with the corresponding synthetic fragments of Inaba O-PS. IgG1s S-20-4 and A-20-6 have absolute affinity constants for synthetic Ogawa mono- to hexasaccharides of from approximately 10(5) to approximately 10(6) M-1. For IgG1s S-20-4, A-20-6, and IgA 2D6, the nonreducing terminal residue of Ogawa O-PS is the dominant determinant, accounting for approximately 90% of the maximal binding energy shown by these antibodies. Binding studies of derivatives of the Ogawa monosaccharide and IgGs S-20-4 and A-20-6 revealed that the C-2 O-methyl group fits into a somewhat flexible antibody cavity and that hydrogen bonds involving the oxygen and, respectively, the OH at the 2- and 3-position of the sugar moiety as well as the 2'-position in the amide side chain are required. Monoclonal IgA ZAC-3 and IgG3 I-24-2 are specific for V. cholerae O:1 serotypes Ogawa/Inaba-LPS.1 The former did not show binding with members of either series of the synthetic ligands related to the O-antigens of the Ogawa or Inaba serotypes, in agreement with its reported specificity for the lipid/core region (1). Inhibition studies revealed that the binding of purified IgG3 I-24-2 to Ogawa-LPS might be mediated by a region in the junction of the OPS to the lipid-core region of the LPS. cDNA cloning and analysis of the anti-Ogawa antibodies S-20-4, A-20-6, and 2D6 revealed a very high degree of homology among the heavy chains. Among the light chains, no such homology between S-20-4 and A-20-6 on the one hand, and 2D6 on the other hand, exists. For the anti-Inaba/Ogawa antibodies I-24-2 and ZAC-3, their heavy chains are completely different, with some homology among the light chains.
Amino Acid Sequence↗
Investigational vaccine for Escherichia coli O157: phase 1 study of O157 O-specific polysaccharide-Pseudomonas aeruginosa recombinant exoprotein A conjugates in adults.
Escherichia coli O157 causes severe enteritis and the extraintestinal complication hemolytic-uremic syndrome. Serum IgG against the surface polysaccharide antigen, the O-specific polysaccharide of lipopolysaccharide (LPS), may confer protective immunity by lysing the inocula. In a phase 1 clinical study, three investigational vaccines were studied in 87 healthy adults. The vaccines were prepared by covalently binding E. coli O157 O-specific polysaccharide with Pseudomonas aeruginosa recombinant exoprotein A. No significant reactions were reported. Most volunteers (81%) responded with a > 4-fold increase in IgG LPS antibodies 1 week after vaccination; all volunteers responded with a > 4-fold rise at 4 weeks and this level was sustained for 26 weeks after injection. All three vaccines elicited high titers of serum bactericidal activity that roughly correlated with the serum IgG and IgM LPS antibody levels. A phase 2 study in young children is planned.
ADP Ribose Transferases↗
Immunization of children with pertussis toxoid decreases spread of pertussis within the family.
OBJECTIVE: In a previously reported double blind placebo-controlled trial it was shown that vaccination with pertussis toxoid during infancy reduced the incidence of pertussis in the vaccinees. Parents and siblings of participants in the trial were followed for pertussis to determine whether vaccination provided indirect protection of close contacts in a nonvaccinating country with a high incidence of pertussis. STUDY DESIGN: A group of 3450 infants were randomized to vaccination with diphtheria, tetanus and pertussis toxoids (DTPtxd) or to diphtheria and tetanus toxoids (DT). Pertussis cases were actively sought and diagnosed by cultures and serology in vaccinees (previously reported) and in family members during 2 years after the third vaccination. RESULTS: Pertussis as defined by the World Health Organization (paroxysmal cough of > or = 21 days and certain laboratory criteria) was diagnosed in 11 parents of DTPtxd recipients and in 26 parents of DT recipients; indirect protection was 60% (95% confidence intervals, 16 to 82%). In nonvaccinated younger siblings of DTPtxd and DT recipients there were 10 and 18 cases of pertussis, respectively; indirect protection was 43% (95% confidence intervals, -31 to 76%). When all cases of pertussis with cough > or = 7 days were included, the indirect protection was 44% (95% confidence intervals, 7 to 67%) in parents and 56% (95% confidence intervals, 9 to 81%) in younger siblings. CONCLUSION: Vaccination of children with pertussis toxoid reduces spread of pertussis to close contacts, which suggests that mass vaccination with pertussis toxoid would induce herd immunity.
Family Health↗
Synthesis and characterization of lipooligosaccharide-based conjugates as vaccine candidates for Moraxella (Branhamella) catarrhalis.
Moraxella (Branhamella) catarrhalis is an important cause of otitis media and sinusitis in children and of lower respiratory tract infections in adults. Lipooligosaccharide (LOS) is a major surface antigen of the bacterium and elicits bactericidal antibodies. Treatment of the LOS from strain ATCC 25238 with anhydrous hydrazine reduced its toxicity 20,000-fold, as assayed in the Limulus amebocyte lysate (LAL) test. The detoxified LOS (dLOS) was coupled to tetanus toxoid (TT) or high-molecular-weight proteins (HMP) from nontypeable Haemophilus influenzae through a linker of adipic acid dihydrazide to form dLOS-TT or dLOS-HMP. The molar ratios of dLOS to TT and HMP conjugates were 19:1 and 31:1, respectively. The antigenicity of the two conjugates was similar to that of the LOS, as determined by double immunodiffusion. Subcutaneous or intramuscular injection of both conjugates elicited a 50- to 100-fold rise in the geometric mean of immunoglobulin G (IgG) to the homologous LOS in mice after three injections and a 350- to 700-fold rise of anti-LOS IgG in rabbits after two injections. The immunogenicity of the conjugate was enhanced by formulation with monophosphoryl lipid A plus trehalose dimycolate. In rabbits, conjugate-induced antisera had complement-mediated bactericidal activity against the homologous strain and heterologous strains of M. catarrhalis. These results indicate that a detoxified LOS-protein conjugate is a candidate for immunization against M. catarrhalis diseases.
Animals↗
Phase 1 evaluation of Vibrio cholerae O1, serotype Inaba, polysaccharide-cholera toxin conjugates in adult volunteers.
Conjugate vaccines were prepared by binding hydrazine-treated lipopolysaccharide (DeALPS) from Vibrio cholerae O1, serotype Inaba, to cholera toxin (CT) variants CT-1 and CT-2. Volunteers (n = 75) were injected with either 25 microg of DeALPS, alone or as a conjugate, or the licensed cellular vaccine containing 4 x 10(9) organisms each of serotypes Inaba and Ogawa per ml. No serious adverse reactions were observed. DeALPS alone did not elicit serum LPS or vibriocidal antibodies in mice and only low levels of immunoglobulin M (IgM) anti-LPS in the volunteers. Recipients of the cellular vaccine had the highest IgM anti-LPS levels, but the difference was not statistically significant from that elicited by the conjugates. The conjugates elicited the highest levels of IgG anti-LPS (DeALPS-CT-2 > DeALPS-CT-1 > cellular vaccine). Both conjugates and the cellular vaccine elicited vibriocidal antibodies: after 8 months, recipients of cellular vaccine had the highest geometric mean titer (1,249), followed by DeALPS-CT-2 (588) and DeALPS-CT-1 (330). The correlation coefficient between IgG anti-LPS and 2-mercaptoethanol (2-ME)-resistant vibriocidal antibodies was 0. 81 (P = 0.0004). Convalescent sera from cholera patients had a mean vibriocidal titer of 2,525 that was removed by treatment with 2-ME. The vibriocidal activities of sera from all vaccine groups and from the patients were absorbed (>75%) by LPS but not by either CT-1 or CT-2. Conjugate-induced IgG vibriocidal antibodies persisted longer than those elicited by the whole-cell vaccine. Both conjugates, but not the cellular vaccine, elicited IgG anti-CT.
Adolescent↗
Standardization of acellular pertussis vaccine by assay of serum neutralizing antibodies to pertussis toxin (antitoxin): analogy with diphtheria toxoid.
Immunity conferred by vaccination with cellular pertussis vaccines and pertussis wanes so that adults are now the main reservoir of B. pertussis. Similar to diphtheria toxoid, acellular pertussis vaccines are suitable for vaccination of adults and it is probable that addition of pertussis toxoid to DT will be recommended for this age group. If this can be achieved, it is easy to predict that pertussis will be eliminated and the possibility of eradicating B. pertussis will become feasible. We propose that, despite the relative inaccuracy of correlating levels of antitoxin with individual immunity, a standardized assay and reference antiserum for pertussis toxoid will control acellular pertussis vaccines as was achieved with diphtheria toxoid.
Adult↗
Standardization may suffice for licensure of conjugate vaccines.
Standardization schemes devised by Control Agencies have followed clinical trials of experimental vaccines. The wealth of information about the pathogenesis of and immunity to bacteria, whose surface polysaccharides are protective antigens, now permits standardization to predict the efficacy of polysaccharide-based vaccines. There has been tacit acceptance of this notion with the licensure of groups Y and W135 meningococcal vaccines and of many of the pneumococcal types whose frequency in patients was too low for statistical significance to be assigned for their clinical efficacy. In fact, this was also the case for licensure of polio virus type 2 vaccine. We can reliably measure the level of anti-polysaccharide antibodies for meningococci, pneumococci, GBS and the Vi of S. typhi. Haemophilus type b conjugates have been reliably standardized by physico-chemical assays. New conjugates, therefore, may be licensed by data provided by standardization without awaiting the results of costly and time-consuming efficacy trials. Adoption of this scientifically-based approach to licensure will hasten the implementation of new and more effective vaccines.
Bacterial Vaccines↗
Measurement of human serum IgG antibodies or a surrogate is sufficient to standardize (predict efficacy) vaccines.
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Adult↗
Immunity to pertussis. Not all virulence factors are protective antigens.
As with diphtheria, immunity to pertussis is complex because it involves both individual and community protection against infection with B. pertussis. Although B. pertussis has at least five proteins required for virulence and an additional two "toxic" components, only serum neutralizing antibodies to PT (antitoxin) have been shown to confer immunity to pertussis.
Bordetella pertussis↗
"Love's labours lost": failure to implement mass vaccination against group A meningococcal meningitis in sub-Saharan Africa.
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Africa South of the Sahara↗
Double-blind vaccine-controlled randomised efficacy trial of an investigational Shigella sonnei conjugate vaccine in young adults.
BACKGROUND: The aim of this double-blind randomised vaccine-controlled trial was to assess the efficacy of a conjugate vaccine composed of Shigella sonnei O-specific polysaccharide bound to Pseudomonas aeruginosa recombinant exoprotein A (S sonnei-rEPA) and of an oral, live-attenuated Escherichia coli/S flexneri 2a (EcSf2a-2) hybrid vaccine among military recruits in Israel at high risk of exposure to Shigella spp. We report here our preliminary findings on the efficacy of S sonnei-rEPA; we have not documented sufficient cases to assess the efficacy of EcSf2a-2. METHODS: Between April, 1993, and August, 1994, male Israeli Military recruits aged 18-22 years were asked to take part in our study. We enrolled 1446 soldiers from seven separate field sites (groups A-G). Soldiers were randomly allocated one injection of S sonnei-rEPA and four doses of oral placebo (n = 576), four oral doses of EcSf2a-2 and one injection of saline placebo (n = 580), or one injection of meningococcal tetravalent control vaccine and four doses of oral placebo (n = 290). Because there were no cases of S flexneri 2a, the EcSf2a-2 and meningococcal vaccines were the control group. We defined S sonnei shigellosis as diarrhoea with a positive faecal culture for S sonnei. Each group of soldiers was followed up for 2.5-7.0 months. The primary endpoint was protective efficacy of S sonnei-rEPA against S sonnei shigellosis. FINDINGS: Cases of culture-proven S sonnei shigellosis occurred in four groups of soldiers (groups A-D), which comprised 787 volunteers (312 received S sonnei-rEPA, 316 received EcSf2a-2, and 159 received meningococcal control vaccine). In groups A-C, cases of shigellosis occurred 70-155 days after vaccination, whereas in group D cases occurred after 1-17 days. In groups A-C, the attack rate of shigellosis was 2.2% in recipients of S sonnei-rEPA compared with 8.6% in controls (protective efficacy 74% [95% CI 28-100], p = 0.006). S sonnei-rEPA also showed significant protection against shigellosis in group D (43% [4-82], p = 0.039). Prevaccination and postvaccination ELISA measurements of antibody to S sonnei lipopolysaccharide among recipients of S sonnei-rEPA showed that the vaccinees who developed S sonnei shigellosis had significantly lower serum IgG and IgA responses to the homologous lipopolysaccharide than those who did not (p = < 0.05). INTERPRETATION: One injection of S sonnei-rEPA confers type-specific protection against S sonnei shigellosis. The high antibody concentration induced by the conjugate vaccine in volunteers who did not develop shigellosis suggests that there is an association between serum antibody titre and protection.
Adolescent↗
Efficacy of a monocomponent pertussis toxoid vaccine after household exposure to pertussis.
In a double-blind, placebo-controlled efficacy trial of a monocomponent pertussis toxoid vaccine, 3450 infants were randomly assigned to vaccination with diphtheria-tetanus toxoids with or without pertussis toxoid at 3, 5, and 12 months of age. Study children and family members were investigated for possible pertussis with cultures, serology, and polymerase chain reaction. Efficacy was 71% after 3 dose when the World Health Organization case definition of pertussis (which includes paroxysmal cough for 21 days or longer) was used. We report the efficacy in the subgroup of children who were exposed to pertussis in the household. Among study children exposed to pertussis in the household from the day of the third vaccination, 20 of 99 (20%) recipients of diphtheria-tetanus-pertussis toxoids vaccine and 64 of 79 (81%) recipients of diphtheria-tetanus toxoids vaccine had pertussis fulfilling criteria of the World Health Organization. The vaccine efficacy was 75% (95% confidence intervals 64% to 84%). In children who had received only two doses at the time of household exposure, vaccine efficacy was 66% (95% confidence intervals 15% to 90%) based on 4 cases among 32 household-exposed recipients of diphtheria-tetanus-pertussis toxoids vaccine and 13 cases among 35 household-exposed recipients of diphtheria-tetanus toxoids vaccine. In conclusion, the pertussis toxoid vaccine provides protection against pertussis both after household and community exposure.
Diphtheria Toxoid↗