John U. Que

Immunogenicity of trivalent subunit versus virosome-formulated influenza vaccines in geriatric patients.

The safety and immunogenicity of a commercial trivalent subunit influenza vaccine and an experimental virosome-formulated influenza vaccine were evaluated among geriatric patients in a double-blind, randomized manner. The virosome vaccine was produced by incorporating hemagglutinin (HA) into the membrane of liposomes composed of phosphatidylcholine. Both vaccines elicited a significant (P < 0.01) rise in the geometric mean anti-HA antibody titer to all three vaccine components 1 month after immunization. However, significantly (P < 0.005) more subjects vaccinated with the virosome preparation mounted a more than fourfold rise to the A/Singapore and A/Beijing strains compared with those who received subunit vaccine. The percentage of patients who attained protective levels (anti-HA titer > or = 40) of anti-A/Beijing antibody was also significantly (P < 0.005) higher in the virosome group. Subjects who possessed non-protective baseline antibody levels to the A/Singapore and A/Beijing strains were more likely (P < 0.005-0.030) to achieve protective levels after immunization with the virosome vaccine than with the subunit vaccine. Of particular clinical significance was the fact that 68.4% of subjects immunized with the virosome vaccine attained protective levels of antibody to all three vaccine components versus 38% for the subunit vaccine (P = 0.010).

VACCINATION OF CYSTIC FIBROSIS PATIENTS AGAINST PSEUDOMONAS AERUGINOSA REDUCES THE PROPORTION OF PATIENTS INFECTED AND DELAYS TIME TO INFECTION

Introduction: Cystic fibrosis (CF) almost always leads to chronic airway infection with Pseudomonas aeruginosa. Despite advances in antibiotic therapy, after chronic infection rapid deterioration in lung function occurs, increasing morbidity and mortality. Prevention of infection by vaccination is desirable, but earlier trials produced disappointing results. The promising short term immunogenicity and safety of a new P. aeruginosa vaccine prompted us to evaluate its long term efficacy. We conducted a 10-year retrospective analysis of outcomes in a group of vaccinated patients. Materials and Methods: In 1989–1990, 30 young children with CF, mean age 7 years, with no prior history of infection with P. aeruginosa, were vaccinated against P. aeruginosa with a polyvalent conjugate vaccine. We report the follow-up of 26 of these patients from 1989 to 2001. The patients were given yearly vaccine boosters. Comparisons were made with a CF patient control group matched for gender, age and, where possible, genetic mutation. Vaccinated patients and controls were attending a single CF clinic and received the same clinical management throughout the study period. Main outcomes were time to infection, proportion of patients infected, development of P. aeruginosa mucoid phenotype, lung function and body weight. Results: The time to infection with P. aeruginosa was longer in the vaccination group than in the control group, and fewer vaccinated patients than controls became chronically infected (32% versus 72%; P < 0.001). The proportion of mucoid infections was higher in the control group (44%) than in the vaccinated group (25%). Patients ≥18 years of age at the end of the study had a lower mean forced expiratory volume at 1 s (FEV1) than did those 13–17 years of age, but this difference was small in the vaccinated group (73.6% versus 83.7%) compared with the controls (48.0% versus 78.7%). In the ≥18 year age category the mean FEV1% at 10 years was 73.6% (vaccinated) and 48.0% (controls) (P < 0.05). In the vaccinated group only 11 (44%) of 25 patients were underweight at the 10-year follow-up compared with 18 (72%) of 25 at the beginning of the study. In the control group 17 (68%) of 25 patients were underweight at 10-year follow-up compared with 16 (64%) of 25 at the beginning of the study. Conclusion: Regular vaccination of young CF patients for a period of 10 years with a polyvalent conjugate vaccine reduced the frequency of chronic infection with P. aeruginosa. This was associated with better preservation of lung function. Vaccinated patients gained more weight during the study period, a possible indication of an improved overall health status.

Safety and Immunogenicity of Live Oral Cholera and Typhoid Vaccines Administered Alone or in Combination with Antimalarial Drugs, Oral Polio Vaccine, or Yellow Fever Vaccine

The effects of concomitant administration of antimalarial drugs, oral polio vaccine, or yellow fever vaccine on the immune response elicited by the Vibrio cholerae CVD103-HgR and Salmonella typhi Ty21a live oral vaccines were investigated. Healthy adults were immunized with CVD103-HgR alone or combined with Ty21a. Subjects were randomized to simultaneously receive mefloquine, chloroquine or proguanil, or oral polio or yellow fever vaccine. The vibriocidal antibody seroconversion rate was significantly reduced (P = .008) only in the group that received chloroquine with the CVD103-HgR. The geometric mean vibriocidal antibody titer was significantly decreased in the groups that received chloroquine (P = .001) or mefloquine (P = .02) compared with titers in groups that received CVD103-HgR alone. However, similar immunosuppressive effects were not observed in the groups immunized with Ty21a and CVD103-HgR. Only the concomitant administration of proguanil effected a significant (P = .013) decline in the anti-S. typhi lipopolysaccharide antibody response. These results indicate that chloroquine and proguanil should not be simultaneously administered with the CVD103-HgR and Ty21a vaccine strains, respectively.

Effect of high-affinity anti-Pseudomonas aeruginosa lipopolysaccharide antibodies induced by immunization on the rate of Pseudomonas aeruginosa infection in patients with cystic fibrosis

Patients with cystic fibrosis (CF; N = 26) and with no prior history of infection with Pseudomonas aeruginosa were immunized with an octavalent O-polysaccharide-toxin A conjugate vaccine. During the next 4 years, 16 patients (61.5%) remained free of infection and 10 (38.5%) became infected. Total serum antilipopolysaccharide (LPS) antibody levels induced by immunization were comparable in infected and noninfected patients. In contrast, 12 of 16 noninfected versus 3 of 10 infected patients (p = 0.024) mounted and maintained a high-affinity anti-LPS antibody response. When compared retrospectively with the rate in a group of age- and gender-matched, nonimmunized, noncolonized patients with CF, the rate at which P. aeruginosa infections were acquired was significantly lower (p < or = 0.02) among all immunized versus nonimmunized patients during the first 2 years of observation. Subsequently, only those immunized patients who maintained a high-affinity anti-LPS antibody response had a significant reduction (p < or = 0.014) in the rate of infection during years 3 and 4. Smooth, typeable strains of P. aeruginosa predominated among immunized patients; rough, nontypeable strains were most frequently isolated from nonimmunized patients. Mucoid variants were isolated from one immunized patient versus six nonimmunized patients. These results indicate that the induction of a high-affinity P. aeruginosa anti-LPS antibody response can influence the rate of infection in patients with CF.

A virosome vaccine antigen delivery system does not stimulate an antiphospholipid antibody response in humans.

A virosome vaccine delivery system comprised of the hemagglutinin of influenza A virus incorporated into unilamellar liposomes consisting of phosphatidylethanolamine (PE) and phosphatidylcholine (PC) or only PC was developed. The anti-PE and anti-PC antibody response was determined for human volunteers immunized with a virosome-formulated vaccine against hepatitis A, or a standard or virosome-formulated influenza vaccine. None of the 100 young adults who received two doses of the hepatitis A vaccine 1 year apart mounted a significant (greater than fourfold) antiphospholipid antibody response. Immunization with a single dose of trivalent influenza vaccine engendered a significant anti-PC and anti-PE antibody response in 1 of 32 elderly nursing home residents who received the virosome-formulated influenza vaccine and in 1 of the 31 residents who received a commercial subunit vaccine. These findings indicate that the virosome system can potentiate the human immune response to vaccine antigens without a concomitant rise in antiphospholipid antibodies.

Safety and immunogenicity of a V3 loop synthetic peptide conjugated to purified protein derivative in HIV-seronegative volunteers.

Objectives: To develop a peptide‐based model for a preventive vaccine for HIV‐1 infection. Design: Phase I trial in HIV‐1‐seronegative volunteers. Participants: Adult healthy subjects HIV‐1‐antibody‐seronegative in an enzymelinked immunosorbent assay, screened for tuberculin [purified protein derivative (PPD)] reactivity with 2 tuberculin units PPD‐administered intradermally. Interventions: Submicrogram doses of a PPD conjugate with a peptide of the primary neutralizing domain (PND) of HIV‐1MN (PPD‐MN‐PND) were administered intradermally to tuberculin skin‐test‐positive and ‐negative volunteers. Results: Antibodies to the MN‐PND were measured after two immunizations in 10 out of 11 PPD skin‐test‐positive volunteers. After the fourth immunization high‐affinity antibodies were detected, which persisted for over 1 year. High titers of MN‐PND‐specific immunoglobulin (Ig) G and IgA were detected in the serum and saliva of all volunteers tested. Serum antibodies were cross‐reactive with PND peptide from some other HIV‐1 strains but neutralized only the HIV‐1MN prototype. Human leukocyte antigen (HLA)‐B7‐restricted MN‐PND‐specific cytotoxic T lymphocytes (CTL) were also detected. Conclusions: The PPD‐MN‐PND vaccine at submicrogram doses is safe and immunogenic in PPD skin‐test‐positive healthy adult volunteers. Long lasting humoral immune responses in the serum and saliva were possibly accompanied by HLA‐B7‐restricted CTL responses. This is a vaccine prototype that can be rapidly and inexpensively modified to include other peptide epitopes. It is especially suitable for use in a worldwide multibillion Bacillus Calmette‐Guérin (BCG)‐primed or tuberculosis‐exposed population at risk for HIV‐1 infection.

Phase 1 trial of a 24-valent Klebsiella capsular polysaccharide vaccine and an eight-valent Pseudomonas O-polysaccharide conjugate vaccine administered simultaneously

A Klebsiella (K) vaccine consisting of 24 capsular polysaccharide antigens and a Pseudomonas aeruginosa (P) vaccine consisting of eight O-polysaccharide antigens conjugated to P toxin A have been developed to prevent sepsis by means of active or passive immunoprophylaxis. In search for a practical immunization schedule, the two vaccines were injected in opposite arms simultaneously (20 volunteers) or 14 days apart (21 volunteers). The vaccines were similarly well tolerated by both volunteer groups. Geometric mean antibody concentrations and mean fold antibody rises to the 33 vaccine antigens (including toxin A) were similar in the two groups at 2 months, and the decline in antibody measured at 18 months was also similar. Because the two vaccines were safe and similarly immunogenic in the two vaccine groups, they can be administered simultaneously to patients or plasma donors in a practical vaccination schedule.

Immunotherapy of sepsis: flawed concept or faulty implementation?

Gram-negative bacillary sepsis is a leading cause of death among patients hospitalized in intensive care units. While initial clinical studies with the passive administration of anti-endotoxin core-glycolipid (CGL) antibodies for the treatment and prophylaxis of sepsis showed promising results, subsequent studies failed to show a consistent benefit. There appears to be a good correlation between anti-CGL antibody levels at the onset of sepsis and maintenance of antibody levels during sepsis with outcome. Previous clinical studies may have failed because insufficient amounts of antibody were administered early in the course of sepsis. Unlike the case with anti-CGL antibodies, polyvalent, hyperimmune type-specific antibody preparations may prevent the development of infections; however, these antibodies also must be provided in adequate amounts and in close proximity to infection in order to provide a beneficial effect. These pharmacokinetic requirements may limit the utility of passive immunotherapy for the prophylaxis of sepsis. Active immunization of acutely traumatized patients or of rats subsequently rendered neutropenic with cyclophosphamide induced high antibody levels for extended periods of time. Since trauma and other conditions are associated with a Th(2) response, these conditions may favor antibody formation following active immunization. Active immunization with both anti-CGL and/or polyvalent-specific vaccines for the prophylaxis of sepsis with passive supplementation at the onset of sepsis is an approach that merits further investigation.

Local and systemic immune responses to combined Vibrio cholerae CVD103-HgR and Salmonella typhi Ty21a live oral vaccines after primary immunization and reimmunization.

The local and systemic antibody responses elicited following concomitant primary immunization and reimmunization with the live oral attenuated Vibrio cholerae CVD103-HgR and Salmonella typhi Ty21a vaccine strains were determined in healthy adult volunteers. A more pronounced serum vibriocidal antibody response was generated after primary immunization compared to reimmunization 2.5 or 3.5 yr later. The seroconversion rate (> or =4-fold rise over baseline) was 81% subsequent to primary immunization versus 57% (p=0.018) and 65% (p=0.639) upon reimmunization at 2.5 and 3.5 yr, respectively. A similar trend was observed for serum anti-S. typhi lipopolysaccharide (LPS) antibodies. After primary immunization, 48% of subjects manifested a significant rise in coproantibody levels to V. cholerae LPS while 60% did so for cholera toxin (CT). Upon reimmunization, the response rate for LPS ranged from 38% at 2.5 yr to 56% at 3.5 yr (p>0.05), while that for CT varied from 31% (p=0. 007) to 50% (p=0.541) at 2.5 and 3.5 yr, respectively. The anti-S. typhi IgA coproantibody response rate was 70% subsequent to primary immunization versus 47% at 2.5 yr (p=0.021) and 63% at 3.5 yr (p=0. 77).

Human immunodeficiency virus-1 principal neutralizing domain peptide-toxin A conjugate vaccine

To enhance the potential efficacy of peptide-based vaccines for human immunodeficiency virus-1 (HIV-1), a principal neutralizing domain (PND) peptide (KRIHIGPGRAFYT) (HIV-1MN) was covalently coupled to Pseudomonas aeruginosa toxin A (TA). Immunization of guinea-pigs with this conjugate vaccine, in the absence of an adjuvant, engendered a high-affinity antibody response to the homologous HIV-1MN PND peptide and to analogous peptides from variant strains of HIV-1. A substantial proportion of such antibodies was directed to the conserved GPGRAF motif. Anti-PND peptide antibodies were capable of neutralizing the homologous strain, HIV-1MN, in addition to two heterologous (RF, IIIB) variants, as determined either by inhibition of syncytia formation or by suppression of p24 antigen production in cultured cells. Therefore, the method of conjugation used preserved critical neutralizing epitopes expressed by the PND peptide. Monovalent or polyvalent PND-TA conjugates, which meet all safety criteria for human use, are a promising approach towards the development of an acquired immunodeficiency syndrome (AIDS) vaccine.