Showing papers on "Vaccination published in 1998"

The Efficacy of Live Attenuated, Cold-Adapted, Trivalent, Intranasal Influenzavirus Vaccine in Children

Abstract: Background Influenzavirus vaccine is used infrequently in healthy children, even though the rates of influenza in this group are high. We conducted a multicenter, double-blind, placebo-controlled trial of a live attenuated, cold-adapted, trivalent influenzavirus vaccine in children 15 to 71 months old. Methods Two hundred eighty-eight children were assigned to receive one dose of vaccine or placebo given by intranasal spray, and 1314 were assigned to receive two doses approximately 60 days apart. The strains included in the vaccine were antigenically equivalent to those in the inactivated influenzavirus vaccine in use at the time. The subjects were monitored with viral cultures for influenza during the subsequent influenza season. A case of influenza was defined as an illness associated with the isolation of wild-type influenzavirus from respiratory secretions. Results The intranasal vaccine was accepted and well tolerated. Among children who were initially seronegative, antibody titers increased by a fac...

Vaccination against Lyme Disease with Recombinant Borrelia burgdorferi Outer-Surface Lipoprotein A with Adjuvant

Abstract: Background The risk of acquiring Lyme disease is high in areas in which the disease is endemic, and the development of a safe and effective vaccine is therefore important. Methods We conducted a multicenter, double-blind, randomized trial involving 10,936 subjects who lived in areas of the United States in which Lyme disease is endemic. Participants received an injection of either recombinant Borrelia burgdorferi outer-surface lipoprotein A (OspA) with adjuvant or placebo at enrollment and 1 and 12 months later. In cases of suspected Lyme disease, culture of skin lesions, polymerase-chain-reaction testing, or serologic testing was done. Serologic testing was performed 12 and 20 months after study entry to detect asymptomatic infections. Results In the first year, after two injections, 22 subjects in the vaccine group and 43 in the placebo group contracted definite Lyme disease (P=0.009); vaccine efficacy was 49 percent (95 percent confidence interval, 15 to 69 percent). In the second year, after the third...

Immunogenicity in humans of a recombinant bacterial antigen delivered in a transgenic potato.

Abstract: Compared with vaccine delivery by injection, oral vaccines offer the hope of more convenient immunization strategies and a more practical means of implementing universal vaccination programs throughout the world. Oral vaccines act by stimulating the immune system at effector sites (lymphoid tissue) located in the gut. Genetic engineering has been used with variable success to design living and non-living systems as a means to deliver antigens to these sites and to stimulate a desired immune response. More recently, plant biotechnology techniques have been used to create plants which contain a gene derived from a human pathogen; the resultant plant tissues will accumulate an antigenic protein encoded by the foreign DNA. In pre-clinical trials, we found that antigenic proteins produced in transgenic plants retained immunogenic properties when purified; if injected into mice the antigen caused production of protein-specific antibodies. Moreover, in some experiments, if the plant tissues were simply fed to mice, a mucosal immune response occurred. The present study was conducted as a proof of principle to determine if humans would also develop a serum and/or mucosal immune response to an antigen delivered in an uncooked foodstuff.

The Guillain–Barré Syndrome and the 1992–1993 and 1993–1994 Influenza Vaccines

Abstract: Background The number of reports of influenza-vaccine–associated Guillain–Barre syndrome to the national Vaccine Adverse Event Reporting System increased from 37 in 1992–1993 to 74 in 1993–1994, arousing concern about a possible increase in vaccine-associated risk. Methods Patients given a diagnosis of the Guillain–Barre syndrome in the 1992–1993 and 1993–1994 influenza-vaccination seasons were identified in the hospital-discharge data bases of four states. Vaccination histories were obtained by telephone interviews during 1995–1996 and were confirmed by the vaccine providers. Disease with an onset within six weeks after vaccination was defined as vaccine-associated. Vaccine coverage in the population was measured through a random-digit–dialing telephone survey. Results We interviewed 180 of 273 adults with the Guillain–Barre syndrome; 15 declined to participate, and the remaining 78 could not be contacted. The vaccine providers confirmed influenza vaccination in the six weeks before the onset of Guillain...

Benefits of influenza vaccination for low-, intermediate-, and high-risk senior citizens.

Abstract: Background: Vaccination rates for healthy senior citizens are lower than those for senior citizens with underlying medical conditions such as chronic heart or lung disease. Uncertainty about the benefits of influenza vaccination for healthy senior citizens may contribute to lower rates of utilization in this group. Objective: To clarify the benefits of influenza vaccination among low-risk senior citizens while concurrently assessing the benefits for intermediate- and high-risk senior citizens. Methods: All elderly members of a large health maintenance organization were included in each of 6 consecutive study cohorts. Subjects were grouped according to risk status: high risk (having heart or lung disease), intermediate risk (having diabetes, renal disease, stroke and/or dementia, or rheumatologic disease), and low risk. Outcomes were compared between vaccinated and unvaccinated subjects after controlling for baseline demographic and health characteristics. Results: There were more than 20 000 subjects in each of the 6 cohorts who provided 147 551 person-periods of observation. The pooled vaccination rate was 60%. There were 101 619 person-periods of observation for low-risk subjects, 15 482 for intermediate-risk, and 30 450 for highrisk subjects. Vaccination over the 6 seasons was associated with an overall reduction of 39% for pneumonia hospitalizations (P,.001), a 32% decrease in hospitalizations for all respiratory conditions (P,.001), and a 27% decrease in hospitalizations for congestive heart failure (P,.001). Immunization was also associated with a 50% reduction in all-cause mortality (P,.001). Within the risk subgroups, vaccine effectiveness was 29%, 32%, and 49% for high-, intermediate-, and low-risk senior citizens for reducing hospitalizations for pneumonia and influenza (for high and low risk, P#.002; for intermediate risk, P = .11). Effectiveness was 19%, 39%, and 33% (for each, P#.008), respectively, for reducing hospitalizations for all respiratory conditions and 49%, 64%, and 55% for reducing deaths from all causes (for each, P,.001). Vaccination was also associated with direct medical care cost savings of $73 per individual vaccinated for all subjects combined (P = .002). Estimates of cost savings within each risk group suggest that vaccination would be cost saving for each subgroup (range of cost savings of $171 per individual vaccinated for high risk to $7 for low risk), although within the subgroups these findings did not reach statistical significance (for each, P$.05). Conclusions: This study confirms that healthy senior citizens as well as senior citizens with underlying medical conditions are at risk for the serious complications of influenza and benefit from vaccination. All individuals 65 years or older should be immunized with this vaccine. Arch Intern Med. 1998;158:1769-1776

Safety and immunogenicity of heptavalent pneumococcal vaccine conjugated to CRM197 in United States infants.

Abstract: Objective. To determine the safety and immunogenicity of heptavalent pneumococcal saccharide vaccine (serotypes 4, 6B, 9V, 14, 18C, 19F, 23F) individually conjugated to CRM197 (PNCRM7), administered at 2, 4, 6, and 12 to 15 months of age. Design. Two hundred twelve healthy 2-month-old infants were equally randomized to receive four consecutive doses of PNCRM7 or an investigational meningococcal group C conjugate vaccine, which served as a control. Concomitantly administered routine vaccines were oral polio vaccine and combined diphtheria toxoid, tetanus toxoid, and whole cell pertussis vaccine/Haemophilus influenzae type b vaccine consisting of capsular oligosaccharides conjugated to CRM197 (DTP/HbOC) at 2, 4, and 6 months, and either measles-mumps-rubella vaccine or HbOC at 12 to 15 months. Active safety surveillance was conducted for 3 days after each dose. Antibody concentrations to each of the 7 pneumococcal serotypes were measured by enzyme-linked immunosorbent assay prevaccination, after doses two and three, prebooster, and postbooster. Results. Significantly fewer children experienced local reactions at the PNCRM7 injection site than at the DTP/HbOC site. There was no increase in the incidence or severity of local reactions at the PNCRM7 site with increasing doses of vaccine. Mild to moderate postvaccination fever was common in both the PNCRM7 and control vaccine groups, however DTP/HbOC was administered concurrently. All 7 vaccine serotypes were immunogenic. The kinetics of the immune responses were serotype-specific. After three doses of PNCRM7, between 92% to 100% of children had ≥0.15 μg/mL of antibody, and 51% to 90% achieved a level of ≥1 μg/mL against specific serotypes. A booster dose of PNCRM7 resulted in a brisk anamnestic response to all 7 vaccine serotypes, demonstrating effective stimulation of T-cell memory by the primary series of vaccinations. Conclusion. Primary immunization followed by a booster dose of PNCRM7 seemed to be acceptably safe and resulted in significant rises in antibody to all 7 serotypes. Implications. Studies to assess vaccine efficacy of PNCRM7 for prevention of systemic disease, nasopharyngeal colonization, and acute otitis media are in progress. If PNCRM7 proves to be protective, there is the potential to prevent up to 85% of invasive pneumococcal disease occurring in US children.

Cost-effectiveness Analysis of a Rotavirus Immunization Program for the United States

Abstract: Context.—Rotavirus is the most common cause of severe diarrhea in children, and a live, oral vaccine may soon be licensed for prevention.Objective.—To estimate the economic impact of a national rotavirus immunization program in the United States.Design.—Cost-effectiveness was analyzed from the perspectives of the health care system and society. A decision tree used estimates of disease burden, costs, vaccine coverage, efficacy, and price obtained from published and unpublished sources.Intervention.—The proposed vaccine would be administered to infants at ages 2, 4, and 6 months as part of the routine schedule of childhood immunizations.Main Outcome Measures.—Total costs, outcomes prevented, and incremental cost-effectiveness.Results.—A routine, universal rotavirus immunization program would prevent 1.08 million cases of diarrhea, avoiding 34000 hospitalizations, 95000 emergency department visits, and 227000 physician visits in the first 5 years of life. At $20 per dose, the program would cost $289 million and realize a net loss of $107 million to the health care system—$103 per case prevented. The program would provide a net savings of $296 million to society. Threshold analysis identified a break-even price per dose of $9 for the health care system and $51 for the societal perspective. Greater disease burden and greater vaccine efficacy and lower vaccine price increased cost-effectiveness.Conclusions.—A US rotavirus immunization program would be cost-effective from the perspectives of society and the health care system, although the cost of the immunization program would not be fully offset by the reduction in health care cost of rotavirus diarrhea unless the price fell to $9 per dose.

A vaccine consisting of recombinant Borrelia burgdorferi outer-surface protein A to prevent lyme disease

Abstract: Background Lyme disease is a multisystem inflammatory disease caused by infection with the tick-borne spirochete Borrelia burgdorferi and is the most common vector-borne infection in the United States. We assessed the efficacy of a recombinant vaccine consisting of outer-surface protein A (OspA) without adjuvant in subjects at risk for Lyme disease. Methods For this double-blind trial, 10,305 subjects 18 years of age or older were recruited at 14 sites in areas of the United States where Lyme disease was endemic; the subjects were randomly assigned to receive either placebo (5149 subjects) or 30 μg of OspA vaccine (5156 subjects). The first two injections were administered 1 month apart, and 7515 subjects also received a booster dose at 12 months. The subjects were observed for two seasons during which the risk of transmission of Lyme disease was high. The primary end point was the number of new clinically and serologically confirmed cases of Lyme disease. Results The efficacy of the vaccine was 68 percen...

DNA vaccines with single-chain Fv fused to fragment C of tetanus toxin induce protective immunity against lymphoma and myeloma

Abstract: Vaccination with idiotypic protein protects against B-cell lymphoma, mainly through anti-idiotypic antibody. For use in patients, DNA vaccines containing single-chain Fv derived from tumor provide a convenient alternative vaccine delivery system. However, single-chain Fv sequence alone induces low anti-idiotypic response and poor protection against lymphoma. Fusion of the gene encoding fragment C of tetanus toxin to single-chain Fv substantially promotes the anti-idiotypic response and induces strong protection against B-cell lymphoma. The same fusion design also induces protective immunity against a surface Ig-negative myeloma. These findings indicate that fusion to a pathogen sequence allows a tumor antigen to engage diverse immune mechanisms that suppress growth. This fusion design has the added advantage of overcoming potential tolerance to tumor that may exist in patients.

Polymorphism in the Bordetella pertussis Virulence Factors P.69/Pertactin and Pertussis Toxin in The Netherlands: Temporal Trends and Evidence for Vaccine-Driven Evolution

Abstract: The Bordetella pertussis proteins P.69 (also designated pertactin) and pertussis toxin are important virulence factors and have been shown to confer protective immunity in animals and humans. Both proteins are used in the new generation of acellular pertussis vaccines (ACVs), and it is therefore important to study the degree of antigenic variation in these proteins. Sequence analysis of the genes for P.69 and the pertussis toxin S1 subunit, using strains collected from Dutch patients in the period 1949 to 1996, revealed three P.69 and three S1 variants which show differences in amino acid sequence. Polymorphism in P.69 was confined to a region comprised of repeats and located proximal to the RGD motif involved in adherence to host tissues. Variation in S1 was observed in two regions previously identified as T-cell epitopes. P.69 and S1 variants, identical to those included in the Dutch whole-cell pertussis vaccine (WCV), were found in 100% of the strains from the 1950s, the period when the WCV was introduced in The Netherlands. However, nonvaccine types of P.69 and S1 gradually replaced the vaccine types in later years and were found in ∼90% strains from 1990 to 1996. These results suggest that vaccination has selected for strains which are antigenically distinct from vaccine strains. Analysis of strains from vaccinated and nonvaccinated individuals indicated that the WCV protects better against strains with the vaccine type P.69 than against strains with non-vaccine types (P = 0.024). ACVs contain P.69 and S1 types which are found in only 10% of recent Dutch B. pertussis isolates, implying that they do not have an optimal composition. Our findings cast a new light on the reemergence of pertussis in highly vaccinated populations and may have major implications for the long-term efficacy of both WCVs and ACVs.

Skin immunization made possible by cholera toxin

Abstract: Immunization using an application to the skin surface, without physical penetration by needles, would greatly increase the ease of vaccination. In orally and nasally administered vaccines, the bacterial product cholera toxin (CT) is commonly used to enhance the immune response. We found that when CT was applied to the surface of the skin, it stimulated an immune response to vaccine components such as diphtheria or tetanus toxoids. Immunization can thus be achieved by the simple application of a mixture of CT and vaccine components without penetration or disruption of the skin.

Progress in the development of an HIV-1 vaccine.

Abstract: Containment of the acquired immunodeficiency syndrome (AIDS) epidemic will require an effective human immunodeficiency virus type 1 (HIV-1) vaccine. Accumulating evidence suggests that such a vaccine must efficiently elicit an HIV-1-specific cytotoxic T lymphocyte (CTL) response. Nonhuman primate models will continue to provide an important tool for assessing the extent of protective immunity induced by various immunization strategies. Although replication-competent AIDS viruses attenuated for pathogenicity by selective gene deletions have provided protective immunity in nonhuman primate models, the long-term safety of such vaccines in human populations is suspect. Inactivated virus and subunit vaccines have elicited neither CTLs nor antibodies capable of neutralizing a wide array of patient HIV-1 isolates. Considerable effort is now being focused on evaluating live vector-based vaccine and plasmid DNA vaccine approaches for preventing HIV-1 infection both in animal model and human studies. Our growing understanding of the biology of HIV-1 and immune responses to this virus will continue to suggest improved vaccination approaches for exploration.

Evaluation of New Vaccines in the Mouse and Guinea Pig Model of Tuberculosis

Abstract: The results of this study provide the first evidence that two completely separate vaccine approaches, one based on a subunit vaccine consisting of a mild adjuvant admixed with purified culture filtrate proteins and enhanced by the cytokine interleukin-2 and the second based on immunization with DNA encoding the Ag85A protein secreted by Mycobacterium tuberculosis, could both prevent the onset of caseating disease, which is the hallmark of the guinea pig aerogenic infection model. In both cases, however, the survival of vaccinated guinea pigs was shorter than that conferred by Mycobacterium bovis BCG, with observed mortality of these animals probably due to consolidation of lung tissues by lymphocytic granulomas. An additional characteristic of these approaches was that neither induced skin test reactivity to commercial tuberculin. These data thus provide optimism that development of nonliving vaccines which can generate long-lived immunity approaching that conferred by the BCG vaccine is a feasible goal.

Deficiency of the Humoral Immune Response to Measles Vaccine in Infants Immunized at Age 6 Months

Abstract: Context.— Measles causes serious morbidity in infants, with the highest risk among those who are 6 to 12 months of age. In the United States, measles vaccine has been given at age 12 to 15 months to minimize interference by passive antibodies and to achieve the high seroprevalence required for herd immunity. Infants of mothers with vaccine-induced immunity may lose passively acquired antibodies before 12 months, leaving them susceptible to measles infection. Objective.— To assess the immunogenicity of measles vaccine in infants younger than 12 months. Design.— Cohort study conducted before and after measles immunization. Setting.— Pediatric clinic in Palo Alto, Calif. Participants.— Infants 6 (n = 27), 9 (n = 26), and 12 (n = 34) months of age were enrolled; 72 provided both initial and follow-up samples. Main Outcome Measures.— Evaluation of immunogenicity before and 12 weeks after measles vaccination, including measles neutralizing antibody titers, measlesspecific T-cell proliferation, and cytokine profiles. Results.— Measles neutralizing antibodies were present before vaccination in 52% (12/23), 35% (7/20), and 0% (0/22) of 6-, 9-, and 12-month-old infants, respectively. In the absence of detectable passive antibodies, geometric mean titers after vaccination were significantly lower in 6-month-old infants compared with 9-month-old infants (27 vs 578, P = .01) and 12-month-old infants (27 vs 972, P = .001). The seroconversion rate, defined as a 4-fold rise in antibody titer, in these 6-month-old infants was only 67%, and only 36% of these infants achieved seroprotective neutralizing antibody titers of 120 or higher after vaccination compared with 100% of 9- and 12-month-old infants lacking detectable passive antibody prior to vaccination. T-cell proliferation and cytokine responses to measles did not differ with age. Conclusions.— Humoral immunity was deficient in 6-month-old infants given measles vaccine, even in the absence of detectable passively acquired neutralizing antibodies. Comparison of their responses with those of 9- and 12-month-old infants indicates that a developmental maturation of the immune response to measles may occur during the first year of life, which affects the immunogenicity of measles vaccine. JAMA. 1998;280:527-532 THE SUSCEPTIBILITY of infants to serious disease caused by viruses is recognized during the immediate neonatal period but it also extends through the first year of life, suggesting that immunocompetence of the host develops gradually over this time interval. In the case of measles, clinical experience demonstrates that a critical maturation of the host response occurs between 6 and 12 months, based on the subsequent decline in measles mortality.

Long-Term Efficacy and Immune Responses following Immunization with the RTS,S Malaria Vaccine

Abstract: The malaria sporozoite vaccine candidate RTS,S, formulated with an oil-in-water emulsion plus the immunostimulants monophosphoryl lipid A and the saponin derivative QS21 (vaccine 3), recently showed superior efficacy over two other experimental formulations. Immunized volunteers were followed to determine the duration of protective immune responses. Antibody levels decreased to between one-third and one-half of peak values 6 months after the last dose of vaccine. T cell proliferation and interferon-gamma production in vitro were observed in response to RTS,S or hepatitis B surface antigen. Seven previously protected volunteers received sporozoite challenge, and 2 remained protected (1/1 for vaccine 1, 0/1 for vaccine 2, and 1/5 for vaccine 3). The prepatent period was 10.8 days for the control group and 13.2 days for the vaccinees (P < .01). Immune responses did not correlate with protection. Further optimization in vaccine composition and/or immunization schedule will be required to induce longer-lasting protective immunity.

Phase I/IIa Safety, Immunogenicity, and Efficacy Trial of NYVAC-Pf7, a Pox-Vectored, Multiantigen, Multistage Vaccine Candidate for Plasmodium falciparum Malaria

Abstract: Candidate malaria vaccines have failed to elicit consistently protective immune responses against challenge with Plasmodium falciparum. NYVAC-Pf7, a highly attenuated vaccinia virus with 7 P. falciparum genes inserted into its genome, was tested in a phase I/IIa safety, immunogenicity, and efficacy vaccine trial in human volunteers. Malaria genes inserted into the NYVAC genome encoded proteins from all stages of the parasite's life cycle. Volunteers received three immunizations of two different dosages of NYVAC-Pf7. The vaccine was safe and well tolerated but variably immunogenic. While antibody responses were generally poor, cellular immune responses were detected in >90% of the volunteers. Of the 35 volunteers challenged with the bite of 5 P. falciparum - infected Anopheles mosquitoes, 1 was completely protected, and there was a significant delay in time to parasite patency in the groups of volunteers who received either the low or high dose of vaccine compared with control volunteers.

Vaccine requirements for sustained cellular immunity to an intracellular parasitic infection

Abstract: The humoral immunity induced by many viral and bacterial vaccines mediates protection that is maintained over a long period of time. In contrast, for other intracellular infections (such as with Leishmania major or Mycobacterium tuberculosis) for which cell-mediated immunity is required for protection, the mechanisms for developing durable responses after vaccination have not been well defined. Here we demonstrate that vaccination with plasmid DNA encoding a specific leishmanial antigen is more effective than leishmanial protein plus recombinant IL-12 in eliciting long-term immunity capable of controlling L. major infection. We also show that leishmanial protein plus IL-12 DNA produces an immunity that lasts much longer than does immunity elicited by leishmanial protein plus IL-12 protein, indicating that the persistence of IL-12 may be the essential determinant in maintaining durable cell-mediated immune responses for an intracellular parasitic infection.

Induction of Immunologic Memory by Conjugated vs Plain Meningococcal C Polysaccharide Vaccine in Toddlers: A Randomized Controlled Trial

Abstract: Context.—Meningococcal polysaccharide vaccines are not used routinely in infants and toddlers, the groups at highest risk of invasive disease, because of poor immunologic responses to the Neisseria meningitidis serogroup C polysaccharide in these age groups. Meningococcal C conjugate vaccines offer the prospect of circumventing this problem.Objective.—To assess the immunogenicity and the induction of immunologic memory in toddlers by meningococcal C conjugate vaccine.Design.—A multicenter, randomized, observer-blinded controlled trial.Setting.—Urban and suburban family medicine or pediatric practices.Participants.—Two hundred eleven healthy toddlers aged 15 to 23 months.Intervention.—Two injections at 2 months apart of meningococcal C conjugate (group 1, n=69), plain meningococcal polysaccharide (group 2, n=72), or hepatitis B virus vaccine (group 3, n=70). All toddlers received a follow-up dose of plain meningococcal polysaccharide vaccine 12 months later.Main Outcome Measures.—IgG meningococcal C anticapsular antibody concentrations determined by enzyme-linked immunosorbent assay and complement-mediated bactericidal antibody.Results.—In group 1, the magnitude of the IgG response to meningococcal C conjugate vaccine was more than 4-fold higher after dose 1 and more than 10-fold higher after dose 2 compared with meningococcal polysaccharide vaccine (group 2) (P<.001). Higher titers persisted in the meningococcal C conjugate group for at least 12 months (P<.001). Group 1, primed with meningococcal C conjugate, had 25-fold higher IgG responses to the meningococcal polysaccharide 1-year booster dose than the controls who had received hepatitis B virus vaccine initially and were given meningococcal polysaccharide vaccine 1 year later for the first time (P<.001). In contrast, group 2, primed with meningococcal polysaccharide, had a 2-fold lower response to the 1-year booster meningococcal polysaccharide dose than the hepatitis B virus control group (P=.006). Serum bactericidal responses paralleled the enzyme-linked immunosorbent assay responses.Conclusions.—Immunization of toddlers with meningococcal C conjugate vaccine induces high titers of anticapsular and bactericidal antibody. Furthermore, this vaccine induces immunologic memory to meningococcal C polysaccharide. In contrast, meningococcal polysaccharide vaccine is less immunogenic than the conjugate vaccine and also induces a hyporesponsive state that persists for at least 12 months.

Identification of Highly Attenuated Mutants of Simian Immunodeficiency Virus

Abstract: Attempts to develop a vaccine for the prevention of AIDS in humans have relied heavily on macaque monkey models that utilize simian immunodeficiency virus (SIV) (9). SIV closely parallels its human counterpart, human immunodeficiency virus (HIV), in genetic makeup and biological properties. We have used SIVmac239 derived from infectious cloned DNA of defined sequence (16) and uncloned, early-passage SIVmac251 (5, 21) for our vaccine studies. These viruses produce consistently high virus loads that can be readily measured in rhesus monkeys, and they induce AIDS in rhesus monkeys in a time frame suitable for laboratory investigation. These strains resemble primary HIV type 1 (HIV-1) isolates in that they are difficult to neutralize even with sera from infected animals (24). Trials in rhesus monkeys have shown that vaccine protection against SIVmac239 and SIVmac251 is very difficult to achieve even under idealized laboratory conditions. Vaccine trials that have used inactivated whole virus, envelope protein, vaccinia virus recombinants, multivalent vaccinia virus recombinants, and multivalent vaccinia virus recombinants followed by particle boosting have shown little or no protection against challenge by these viruses (7, 10, 22, 26, 30, 31). These vaccine failures have occurred despite extensive attempts to match the strain of challenge virus closely to the vaccine and to time the challenge at or near the peak of vaccine-induced immune responses. In contrast to these vaccine failures, the live attenuated vaccine approach has afforded impressive protection against challenge by SIVmac251 and SIVmac239 (1, 4, 35). Some studies have used vaccine strains with defined attenuating mutations (1, 4, 35), while others have used attenuated or partially attenuated strains whose attenuating mutations have not been defined (2, 23). In our studies, we have demonstrated strong protective immunity by vaccination with SIVmac239Δnef (lacking nef sequences) and SIVmac239Δ3 (lacking nef, vpr, and US [upstream sequences of U3]) (4, 35). The live attenuated vaccine approach has not, however, been universally successful in protecting against SIV (2, 23, 35). The length of time between vaccination and challenge appears to be one variable that influences protective efficacy with the live attenuated approach (35); other factors that determine protective efficacy have not been defined. Most viral vaccines currently in use in humans are live attenuated strains of virus. Extensive experience with the development and testing of these viral vaccines in humans has demonstrated the importance of seeking a critical balance between safety and potency (28). The vaccine strain should be attenuated enough to ensure relative safety in the target population but potent enough to induce good protective immunity. Whether this concept also holds for live attenuated vaccination against SIV and HIV remains to be demonstrated. We have targeted five regions of the SIV genome for attenuating mutations. These five regions are the nef gene, the vpx gene, the vpr gene, the vif gene, and sequences in the upstream region of U3 in the long terminal repeat (US). In all cases, we have used the infectious, pathogenic SIVmac239 clone as the starting parental strain and have introduced large deletions in order to prevent reversion at the targeted locus (12). For deletions involving vpr and vpx, we have demonstrated the normal expression of adjacent open reading frames (11). While US is probably nothing more than nef coding sequence (13, 18, 19), it will be treated as a discrete entity for the purpose of this report. Previous publications have described the properties of Δnef, Δvpr, Δvpx, ΔvprΔvpx, and Δ3 constructs in rhesus monkeys (11, 17, 35). Here we describe the properties of even more highly attenuated strains Δ3x (missing nef, vpx, and US), Δ4 (missing nef, vpr, vpx, and US), and Δvif (missing vif) as they relate to Δ3 and the other strains studied previously.

Distinct T-cell subtypes induced with whole cell and acellular pertussis vaccines in children.

Abstract: Recent clinical trials have demonstrated that new generation acellular pertussis vaccines can confer protection against whooping cough. However, the mechanism of protective immunity against Bordetella pertussis infection induced by vaccination remains to be defined. We have examined cellular immune responses in children immunized with a range of acellular and whole cell pertussis vaccines. Immunization of children with a potent whole-cell vaccine induced B. pertussis-specific T cells that secreted interferon-gamma (IFN-gamma), but not interleukin-5 (IL-5). In contrast, T cells from children immunized with acellular pertussis vaccines secreted IFN-gamma and/or IL-5 following stimulation with B. pertussis antigens in vitro. These observations suggest that protective immunity conferred by whole-cell vaccines, like natural immunity, is mediated by type 1 T cells, whereas the mechanism of immune protection generated with acellular vaccines may be more heterogeneous, involving T cells that secreted type 1 and type 2 cytokines.

Immunological and Virological Analyses of Persons Infected by Human Immunodeficiency Virus Type 1 while Participating in Trials of Recombinant gp120 Subunit Vaccines

Abstract: We have studied 18 participants in phase I/II clinical trials of recombinant gp120 (rgp120) subunit vaccines (MN and SF-2) who became infected with human immunodeficiency virus type 1 (HIV-1) during the course of the trials. Of the 18 individuals, 2 had received a placebo vaccine, 9 had been immunized with MN rgp120, and seven had been immunized with SF-2 rgp120. Thirteen of the 18 infected vaccinees had received three or four immunizations prior to becoming infected. Of these, two were placebo recipients, six had received MN rgp120, and five had received SF-2 rgp120. Only 1 of the 11 rgp120 recipients who had multiple immunizations failed to develop a strong immunoglobulin G antibody response to the immunogen. However, the antibody response to rgp120 was transient, typically having a half-life of 40 to 60 days. No significant neutralizing activity against the infecting strain was detected in any of the infected individuals at any time prior to infection. Antibody titers in subjects infected despite vaccination and in noninfected subjects were not significantly different. Envelope-specific cytotoxic T-lymphocyte responses measured after infection were infrequent and weak in the nine vaccinees who were tested. HIV-1 was isolated successfully from all 18 individuals. Sixteen of these strains had a non-syncytium-inducing (NSI) phenotype, while two had a syncytium-inducing (SI) phenotype. NSI strains used the CCR5 coreceptor to enter CD4+ cells, while an SI strain from one of the vaccinees also used CXCR4. Viruses isolated from the blood of rgp120 vaccinees were indistinguishable from viruses isolated from control individuals in terms of their inherent sensitivity to neutralization by specific monoclonal antibodies and their replication rates in vitro. Furthermore, genetic sequencing of the env genes of strains infecting the vaccinees did not reveal any features that clearly distinguished these viruses from contemporary clade B viruses circulating in the United States. Thus, despite rigorous genetic analyses, using various breakdowns of the data sets, we could find no evidence that rgp120 vaccination exerted selection pressure on the infecting HIV-1 strains. The viral burdens in the infected rgp120 vaccine recipients were also determined, and they were found to be not significantly different from those in cohorts of placebo-vaccinated and nonvaccinated individuals. In summary, we conclude that vaccination with rgp120 has had, to date, no obvious beneficial or adverse effects on the individuals we have studied.

Protective Efficacy of a Live Attenuated Vaccine against Argentine Hemorrhagic Fever

Abstract: Argentine hemorrhagic fever (AHF), caused by the arenavirus Junin, is a major public health problem among agricultural workers in Argentina. A prospective, randomized, double-blind, placebo-controlled, efficacy trial of Candid 1, a live attenuated Junin virus vaccine, was conducted over two consecutive epidemic seasons among 6500 male agricultural workers in the AHF-endemic region. Twenty-three men developed laboratory-confirmed AHF during the study; 22 received placebo and 1 received vaccine (vaccine efficacy 95%; 95% confidence interval [CI], 82%-99%). Three additional subjects in each group developed laboratory-confirmed Junin virus infection associated with mild illnesses that did not fulfill the clinical case definition for AHF, yielding a protective efficacy for prevention of any illness associated with Junin virus infection of 84% (95% CI, 60%-94%). No serious adverse events were attributed to vaccination. Candid 1, the first vaccine for the prevention of illness caused by an arenavirus, is safe and highly efficacious.

Vaccination against Chlamydial Genital Tract Infection after Immunization with Dendritic Cells Pulsed Ex Vivo with Nonviable Chlamydiae

Abstract: Chlamydia trachomatis , an obligate intracellular bacterial pathogen of mucosal surfaces, is a major cause of preventable blindness and sexually transmitted diseases for which vaccines are badly needed. Despite considerable effort, antichlamydial vaccines have proven to be elusive using conventional immunization strategies. We report the use of murine bone marrow–derived dendritic cells (DC) pulsed ex vivo with killed chlamydiae as a novel approach to vaccination against chlamydial infection. Our results show that DC efficiently phagocytose chlamydiae, secrete IL-12 p40, and present chlamydial antigen(s) to infection sensitized CD4+ T cells. Mice immunized intravenously with chlamydial-pulsed DC produce protective immunity against chlamydial infection of the female genital tract equal to that obtained after infection with live organisms. Immunized mice shed ∼3 logs fewer infectious chlamydiae and are protected from genital tract inflammatory and obstructive disease. Protective immunity is correlated with a chlamydial-specific Th1-biased response that closely mimics the immune response produced after chlamydial infection. Thus, ex vivo antigen-pulsed DC represent a powerful tool for the study of protective immunity to chlamydial mucosal infection and for the identification of chlamydial protective antigens through reconstitution experiments. Moreover, these findings might impact the design of vaccine strategies against other medically important sexually transmitted diseases for which vaccines are sought but which have proven difficult to develop.

Immune Responses to Human Immunodeficiency Virus (HIV) Type 1 Induced by Canarypox Expressing HIV-1MN gp120, HIV-1SF2 Recombinant gp120, or Both Vaccines in Seronegative Adults

Abstract: A safety and immunogenicity trial was conducted in vaccinia-immune and vaccinia-naive human immunodeficiency virus (HIV)-uninfected adults who were randomized to receive 10(6) or 10(7) TCID50 of canarypox (ALVAC) vector expressing HIV-1MN gp160 or 10(5.5) TCID50 of ALVAC-rabies virus glycoprotein control at 0 and 1 or 2 months and ALVAC-gp160 or 50 microg of HIV-1SF2 recombinant (r) gp120 in microfluidized emulsion at 9 and 12 months; others received rgp120 at 0, 1, 6, and 12 months. All vaccines were well-tolerated. Neither vaccinia-immune status before vaccination nor ALVAC dose affected HIV immune responses. HIV-1MN and HIV-1SF2 neutralizing antibodies were detected more often (100%) in ALVAC-gp160/rgp120 recipients than in recipients of ALVAC-gp160 (<65%) or rgp120 (89%) alone. ALVAC-gp160/rgp120 also elicited more frequent HIV V3-specific and fusion-inhibition antibodies, antibody-dependent cellular cytotoxicity, lymphoproliferation, and cytotoxic CD8+ T cell activity than did either vaccine alone. Trials with ALVAC expressing additional HIV components and rgp120 are underway.