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Vaccine Comparison

Nontypeable H. influenzae LOS-TT conjugate vaccine Nontypeable H. influenzae Outer Membrane Protein P1 vaccine
Vaccine Information Vaccine Information
  • Vaccine Ontology ID: VO_0000480
  • Type: Conjugate vaccine
  • Antigen: lipooligosaccharide (LOS)
  • Preparation: Tetanus toxoid (TT) was obtained from Pasteur-Merieux Connaught and purified through an S-300 Sephacryl column. LOS was prepared from NTHi strain 9274. It was used for preparation of dLOS and its derivative with adipic acid dehydrazide (AH–dLOS). The fusion dLOS–TT was further synthesized (Gu et al., 2003).
  • Description: Nontypeable Haemophilus influenzae (NTHi) accounts for about one-third of purulent otitis media (OM) in children and is a common cause of pulmonary infection in adults with decreased resistance. Lipooligosaccharide(LOS) is both a virulence factor and a potential protective surface antigen. Human antibodies and mouse monoclonal antibodies against LOS are produced and can be bactericidal for NTHi (Gu et al., 2003).
  • Vaccine Ontology ID: VO_0004110
  • Type: Subunit vaccine
  • Antigen: Outer Membrane Protein P1
  • ompP1 gene engineering:
    • Type: Recombinant protein preparation
    • Detailed Gene Information: Click Here.
  • Adjuvant: Ribi vaccine adjuvant
  • Preparation: OmpP1 was cloned from the clinical NTHI strain BCH-3 and expressed P1 in the cytoplasm of E. coli (rP1BCH-3 ).
  • Description: OMP P1 (47 kDa) accounts for ~10% of H. influenzae OMP content. Passive immunization with P1 induces protection against bacteremia in the infant rat model. OMP P1 has eight potentially surface-exposed loops, four of which are immunogenic. The availability of several ompP1 sequences was particularly relevant, as it offered the information needed for a broader survey of the sequence conservation of the ompP1 gene across a phylogenically classified collection of >500 typeable H. influenzae and NTHI isolates representing the natural population structure of the species (Bolduc et al., 2000).
Host Response Host Response

Human Response

  • Vaccination Protocol: This is a Phase I clinical trial for this vaccine. Forty healthy adult volunteers of either sex, between 18 and 35 years of age, were recruited and informed consent was obtained. All 40 volunteers received an injection in the deltoid muscle with 0.5 mlof the investigational vaccine (25ug saccharide), and 28 of them also received a second injection in 3–4 months after the first injection. Their injection sites and body temperatures along with other reactions were monitored by a medically credentialled provider or nurse before and 1, 6, 24, and 48 h after each injection. Local and systemic reactions were monitored and sera, taken before and 2, 6, 14, 16, and 38 weeks after injection, were assayed for IgG, IgA, and IgM antibodies to the LOS by ELISA and for bactericidal activity (Gu et al., 2003).
  • Immune Response: All volunteers had pre-existing IgG anti-LOS. The geometric mean (GM) level rose from 14 to 40 at 2 weeks, remained at 35 at 6 weeks (40 or 35 versus 14,P <0.01) and dropped to 27 at 14 weeks after the first injection. There was also a rise 2 weeks after the second injection (27 versus 37,P <0.05 ). A total of 52.5% of subjects showed serum-conversion (greater than four-fold increase) after one and two injections. At 38 weeks, the GM IgG anti-LOS was still higher than before initial injection (20 versus 14,P < 0.05). A similar pattern of reactivity was observed for IgA and IgM anti-LOS (Gu et al., 2003).
  • Side Effects: Analysis of the frequency and degree of local signs and symptoms at the injection area showed that all reactions were mild or moderate. There were four subjects complained of mild to moderate pain, one subject showed mild to moderate erythema (1–2 cm), two showed mild to moderate induration (1–2 cm). For systemic reactions, two subjects showed temperatures of 37.6 and 37.7 ◦C after the first injection and one subject reached 37.7 ◦C after the second injection. None reported abdominal discomfort or skin rashes. All other complaints were judged to be mild or moderate and medication was rarely required for the symptoms. There was no significant difference in systemic symptoms between two injections except for the incidence of myalgia (P = 0.039) (Gu et al., 2003).

chinchillas Response

  • Vaccination Protocol: The 58 chinchillas animals were randomly assigned to three groups (saline [n = 19], dLOS-TT [n = 20], and dLOS-HMP [n = 19]), and a blood sample was collected from the transverse venous sinus of each chinchilla to assess antibody levels. Three days later, the animals were immunized with three doses of the two conjugates or saline (as a control) at 4-week intervals. Blood samples were also collected from all of the chinchillas 14 days after the first and second immunizations, 10 days after the third immunization, and before sacrifice. The animals were anesthetized with ketamine-HCl (30 mg/kg of body weight given intramuscularly) prior to all operative procedures (Gu et al., 1997).
  • Immune Response: Three injections of saline did not elicit a rise of LOS antibodies in controls. In contrast, both conjugates elicited significant levels of anti-LOS IgG and IgM antibodies.
  • Challenge Protocol: The animals were challenged by injection of 140 CFU of strain 9274 into the right ME 14 days after the last immunization. Both ears were examined daily by otoscopy for evidence of acute OM for 21 days postchallenge. On days 3, 7, 14, and 21 postchallenge, four or five animals from each group were sacrificed by ketamine injection followed by cervical dislocation and the ME fluids from both ears were cultured for bacterial counting (Gu et al., 1997).
  • Efficacy: All controls developed OM with culture-positive NTHi effusions up to 21 days postchallenge. In contrast, 60% of chinchillas from both conjugate groups developed OM on day 3, 80% did so on day 7, and 60% did so on day 14. On day 21, no animals in the dLOS-TT group and only 50% of the animals in the dLOS-HMP group showed OM with effusions. The incidence of OM was significantly lower in the dLOS-TT group than in the controls on day 21 and over the whole course. There was no significant difference between the dLOS-TT and dLOS-HMP groups.

chinchillas Response

  • Vaccination Protocol: rP1BCH-3 was emulsified in RIBI adjuvant R-730 emulsion (RIBI Immunochem Research) to a final rP1BCH-3 concentration of 125 µg/ml. Twenty-eight chinchillas were immunized with two 0.1-ml intramuscular (i.m.) injections in the hindquarters on days 0, 35, 57, 79, 99, 120, and 141. Eight control chinchillas received two 0.1-ml i.m. injections of RIBI adjuvant only on the same days. All chinchillas were bled by cardiac puncture using a 23-gauge 3-ml syringe on days 0 (before receiving the first immunization) and 148 (prior to challenge) (Bolduc et al., 2000).
  • Challenge Protocol: Seven days after the final immunization, four nonimmunized chinchillas were added to the experimental group as controls. All animals were examined by otoscopy and tympanometry to document healthy, normal middle ears. Loopfuls of wt strain BCH-3 and the isogenic BCH-3 ompP1 mutant were inoculated separately into 1 ml of supplemented brain heart infusion medium and incubated without agitation for 16 to 18 h at 37°C. Overnight cultures were diluted by 2 × 10-3 in Gey's balanced salt solution (Sigma). The chinchillas were divided into two groups. One group was challenged with wt BCH-3, and the other was challenged with the BCH-3 ompP1 mutant by injecting 0.1 ml of the diluted cultures containing 50 to 60 CFU directly into the right middle-ear cavity through the superior bulla with a tuberculin syringe. Chinchillas were reexamined by otoscopy and tympanometry on days 2, 4, 6, 8, 10, 14, and 18. On these days, the middle-ear cavities were also examined through a small (4 mm in diameter) incision in the superior bulla, leaving the tympanic membrane intact. The right middle-ear cavities were cultured by swabbing the cavity with a calcium alginate swab (Calgiswab type 1; Hardwood Products Company LP) and streaking onto chocolate agar plates (Bolduc et al., 2000).
  • Efficacy: all animals developed antibodies specific for rP1. Immunized animals were protected against disease when challenged with BCH-3, but not with an ompP1 mutant of BCH-3 or a strain (BCH-2) possessing a heterologous P1 (91% identity).
References References
Gu et al., 1997: Gu XX, Sun J, Jin S, Barenkamp SJ, Lim DJ, Robbins JB, Battey J. Detoxified lipooligosaccharide from nontypeable Haemophilus influenzae conjugated to proteins confers protection against otitis media in chinchillas. Infection and immunity. 1997; 65(11); 4488-4493. [PubMed: 9353024].
Gu et al., 2003: Gu XX, Rudy SF, Chu C, McCullagh L, Kim HN, Chen J, Li J, Robbins JB, Van Waes C, Battey JF. Phase I study of a lipooligosaccharide-based conjugate vaccine against nontypeable Haemophilus influenzae. Vaccine. 2003 May 16; 21(17-18); 2107-14. [PubMed: 12706701].
Bolduc et al., 2000: Bolduc GR, Bouchet V, Jiang RZ, Geisselsoder J, Truong-Bolduc QC, Rice PA, Pelton SI, Goldstein R. Variability of outer membrane protein P1 and its evaluation as a vaccine candidate against experimental otitis media due to nontypeable Haemophilus influenzae: an unambiguous, multifaceted approach. Infection and immunity. 2000 Aug; 68(8); 4505-17. [PubMed: 10899849].