Safety and immunogenicity of attenuated dengue virus vaccines (Aventis Pasteur) in human volunteers.

A randomized, controlled, double-blinded study was conducted to determine safety and immunogenicity of five live attenuated dengue vaccines produced by Aventis Pasteur (AvP). The study was completed with 40 flavivirus non-immune volunteers: five recipients of each monovalent (dengue-1, dengue-2, dengue-3, or dengue-4) vaccine, ten recipients of tetravalent (dengue-1, dengue-2, dengue-3, and dengue-4) vaccine, and ten recipients of vaccine vehicle alone. All vaccines were administered in a single subcutaneous dose (range, 3.6-4.4 log(10) plaque forming units). No serious adverse reactions occurred in volunteers followed for 6 months after vaccination. Five vaccine recipients developed fever (T > or = 38.0 degrees C), including four tetravalent vaccinees between days 8 and 10 after vaccination. Dengue-1, dengue-2, dengue-3, or dengue-4 vaccine recipients reported similar frequency of mild symptoms of headache, malaise, and eye pain. Tetravalent vaccinees noted more moderate symptoms with onset from study days 8-11 and developed maculopapular rashes distributed over trunk and extremities. Transient neutropenia (white blood cells < 4000/mm3) was noted after vaccination but not thrombocytopenia (platelets < 100,000/mm3). All dengue-3, dengue-4, and tetravalent vaccine recipients were viremic between days 7 and 12 but viremia was rarely detected in dengue-1 or dengue-2 vaccinees. All dengue-2, dengue-3, and dengue-4, and 60% of dengue-1 vaccine recipients developed neutralizing and/or immunoglobulin M antibodies. All tetravalent vaccine recipients were viremic with dengue-3 virus and developed neutralizing antibodies to dengue-3 virus. Seven volunteers also had multivalent antibody responses, yet the highest antibody titers were against dengue-3 virus. The AvP live attenuated dengue virus vaccines are safe and tolerable in humans. The live attenuated tetravalent dengue vaccine was most reactogenic, and preferential replication of dengue-3 virus may have affected its infectivity and immunogenicity.

Growth-inhibiting antibody responses of humans vaccinated with recombinant outer surface protein A or infected with Borrelia burgdorferi or both.

Serial serum samples from a 2-year human trial of outer surface protein (Osp) A vaccine were analyzed by Borrelia burgdorferi growth-inhibition assay (GIA) and anti-OspA ELISA to assess the antibody responses of vaccine recipients and subjects with Lyme disease. Although 74% of OspA recipients had a reciprocal GIA titer >/=64 after 3 vaccinations, none of the placebo recipients, even those with Lyme disease, had a GIA titer this high. The correlation between GIA and ELISA titers after 3 doses of vaccine was.84; however, more vaccine recipients had an elevated ELISA titer paired with low GIA titer than had a low ELISA titer with a high GIA titer. OspA-vaccine recipients who acquired Lyme disease had significantly lower serum GIA and ELISA titers after 3 immunizations than did age- and sex-matched OspA recipients without Lyme disease. Thus, vaccinated subjects had antibodies to native antigen on viable cells, and antibody assays with this specificity may predict protection of vaccinees against infection.

A vaccine consisting of recombinant Borrelia burgdorferi outer-surface protein A to prevent Lyme disease. Recombinant Outer-Surface Protein A Lyme Disease Vaccine Study Consortium.

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 microg 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 percent in the first year of the study in the entire population and 92 percent in the second year among the 3745 subjects who received the third injection. The vaccine was well tolerated. There was a higher incidence of mild, self-limited local and systemic reactions in the vaccine group, but only during the seven days after vaccination. There was no significant increase in the frequency of arthritis or neurologic events in vaccine recipients. CONCLUSIONS: In this study, OspA vaccine was safe and effective in the prevention of Lyme disease.

Clinical and serological responses following primary and booster immunization with Salmonella typhi Vi capsular polysaccharide vaccines.

Clinical and serum antibody responses following intramuscular injection of two formulations of Salmonella typhi Vi capsular polysaccharide (Vi) were assessed in a double-blind evaluation. Healthy adults were randomly assigned to receive a 25 micrograms dose of liquid (Vi-Liq; n = 182) or freeze-dried Vi vaccine (Vi-Lyoph; n = 55), or placebo (n = 86). Erythema and/or induration > or = 1 cm in diameter at the injection site developed in 13/182 (7%) of Vi-Liq and 3/55 (5%) of Vi-Lyoph recipients (not significant, n.s.). Fever (oral temperature > or = 100 degrees F (37.8 degrees C)) occurred in < 2% of vaccinees. The frequencies of rises of fourfold or greater and of maximal Vi antibody levels were similar in the two vaccine groups. Fourfold or greater rises in serum Vi antibody levels (RIA) developed in 53% of Vi-Lyoph and 60% of Vi-Liq recipients by 1 week (n.s.), and 98 and 93%, respectively, by 1 month (n.s.). The frequencies of adverse reactions and mean Vi antibody levels following booster immunization with Vi-Liq 27 to 34 months after primary immunization (n = 55) were similar to those observed following primary immunization, although subjects given a booster dose were more likely to develop local reactions > or = 1 cm in diameter than those given a first dose (10/55 versus 13/182, p = 0.013 by the chi 2 test). Primary and booster immunizations with the Vi vaccines are well tolerated in healthy adults; mean Vi antibody levels remain significantly elevated for up to 34 months after primary immunization.

Effect of oligosaccharide chain length, exposed terminal group, and hapten loading on the antibody response of human adults and infants to vaccines consisting of Haemophilus influenzae type b capsular antigen unterminally coupled to the diphtheria protein CRM197.

Vaccines consisting of oligosaccharide (OS) derived from Haemophilus influenzae type b capsular polysaccharide and conjugated to carrier proteins had been shown capable of eliciting memory-type capsular polysaccharide of H. influenza type b antibody responses in human infants, but the structural variables governing immunogenicity were not defined. Here a series of conjugates were made with the diphtheria protein CRM197 and with uniterminally coupled OS haptens that varied in chain length, exposed terminal residue, or multiplicity of loading as defined by ribose/protein ratio. Adults were given a single injection, 1-yr-old infants were given a two-injection sequence, and capsular polysaccharide of H. influenzae type b antibody responses were assessed by radioantigen binding. Vaccines C-4r, C-6r, and C-12r, in which ribitol-ended OS of mean length 4, 6, or 12 repeat units were coupled at low hapten loading, were about equally immunogenic (geometric means 2 to 5 micrograms/ml in infants, 5 to 9 micrograms/ml in adults). Vaccine C7p was made with a higher loading of OS having mean length 7 repeat units and having mainly phosphate monoester at the exposed termini Vaccine C-7R was made from a portion of C-7p by enzymatic removal of most of the terminal phosphates. Compared to the C-4r, C-6r, and C-12r series, vaccines C-7p and C-7R induced geometric means about 10-fold higher in adults and 20-fold higher in infants. Thus OS chain length (in the range studied) and exposed terminus are less critical variables in this system than the extent of hapten loading.

Antibody response of adults to an aluminum hydroxide-adsorbed Neisseria meningitidis serotype 2b protein-group B polysaccharide vaccine.

A group B Neisseria meningitidis serotype protein vaccine was studied clinically in adults. The vaccine comprised lipopolysaccharide-depleted outer membrane vesicles from a serotype 2b strain, 3006-M2, noncovalently complexed with group B meningococcal polysaccharide. Volunteers received 25 micrograms each of protein and polysaccharide administered intramuscularly either in 0.9% NaCl or adsorbed onto aluminum hydroxide on weeks 0 and 6. Most individuals experienced mild local reactions, but there were no systemic reactions. Both vaccine formulations stimulated antibodies to the outer membrane proteins of serotypes 2a:P1.2 and 2b:P1.2, but higher levels were achieved with the aluminum hydroxide-adsorbed vaccine after two immunizations. Vaccine-induced antibodies were primarily IgG and were bactericidal for both a serotype 2a and a serotype 2b strain. Induction of bactericidal antibodies has been shown to be a major predictor of protection against meningococcal disease.

Immunogenicity of the Haemophilus influenzae type b capsular polysaccharide conjugate vaccine in children after systemic Haemophilus influenzae type b infections.

We immunized 24 patients (mean age 15.2 +/- 9.3 months) with polyribosylribitol phosphate-diphtheria toxoid conjugate vaccine (PRP-D) 2 months after a systemic Haemophilus influenzae type b infection. Children less than 24 months of age were immunized twice. Serum was obtained for antibody to PRP before and 1 or 2 months after immunization. Three of five children greater than 24 months of age and three of six children 18 to 24 months of age developed greater than 1 microgram/ml of antibody after immunization, and geometric mean postimmunization levels were significantly greater than preimmunization levels for both groups. However, two children who failed to respond to conventional PRP vaccine did not respond as expected to one dose of PRP-D. For children 7 to 17 months of age, the geometric mean PRP antibody levels increased as follows: preimmunization, 0.05 micrograms/ml; after the first dose, 0.28 micrograms/ml (p = 0.003); and after the second dose, 3.39 micrograms/ml (p = 0.001). Of 13 children, 10 developed antibody values greater than 1.0 micrograms/ml. PRP conjugate vaccines are immunogenic in young children who have not developed protective PRP antibody levels after a systemic H. Influenzae type b infection.

Safety and immunogenicity of Haemophilus influenzae type b polysaccharide-diphtheria toxoid conjugate vaccine (PRP-D) in infants.

Safety and immunogenicity of a Haemophilus influenzae type b polysaccharide-diphtheria toxoid conjugate vaccine (PRP-D) was evaluated in infants seven to 14 months of age. PRP-D (80% of subjects) or saline placebo (20%) was randomly and blindly administered (two doses separated by two months). Incidence of mild reactions lasting less than 48 hr did not differ significantly between the placebo and vaccine recipients. Preimmunization levels of antibody to PRP were less than or equal to 0.15 micrograms/ml in 97% of subjects. A twofold increase in antibody concentration occurred in 88% of subjects following the first dose and in 99% following the second dose of vaccine. No change occurred in placebo recipients. Mean level of antibody and percentage of subjects with levels of antibody greater than or equal to 1 microgram/ml after vaccination increased with increasing age. Responses were related to vaccine lot but not to sex, race, or geographic location. Two doses of PRP-D in infants seven months of age and older induced antibody levels equal to or greater than levels in infants 24 months of age given the polysaccharide alone.

Adenovirus pneumonia.

Adenoviruses are ubiquitous DNA viruses that cause a wide variety of illnesses, including pneumonia, in children and adults. Forty-one distinct human sero-types have been identified, yet only about six of these serotypes are associated with the majority of the cases of adenovirus-induced pneumonia. Adeno-virus infection accounts for up to 20% of childhood pneumonias, primarily in those children younger than 5 years of age, but such pneumonias occur infrequently in the nonmilitary adult population. Roentgenologic findings include patchy or diffuse infiltrates, consolidation, and occasionally, pleural effusion. Histopathologic examination of lung tissue frequently reveals a necrotizing bronchitis and bronchiolitis. Such pulmonary destruction results in abnormal pulmonary function in up to 60% of these patients. Mortality rates vary with the population studied and the etiologic serotype, reaching as high as 60% in immunocompromised patients and 15% to 20% of the children with adenovirus type 7 pneumonia. Diagnosis requires either virus isolation or detection of a four-fold or greater rise in serum antibody over a 2- to 3-week period of time. Treatment consists primarily of symptomatic care, while prevention of infection relies upon the selected use of serotype-specific, enteric-coated, live adenovirus vaccines.

Safety and immunogenicity of a purified hepatitis B virus vaccine prepared by using recombinant DNA technology.

Forty healthy adult males were given a 20-micrograms intramuscular dose of either a new recombinant hepatitis B virus (HBV) vaccine produced in mammalian cells (rHBsAg) or the currently licensed HBV vaccine derived from human plasma (HEPTAVAX-B), and booster doses were administered one month and six months later. The percentage of vaccinees who seroconverted on the 10th and 30th days after the first vaccination was higher for the rHBsAg vaccinees than for the recipients of plasma-derived vaccine (rHBsAg: 10% on day 10 and 70% on day 30; HEPTAVAX-B: 0% and 25%, respectively). The only statistically significant difference in titers of antibody to HBV surface antigen was noted 30 days after the first vaccination. Both vaccines induced a shift in antibody from the 19S to the 7S fraction and a specific antibody response to the a determinant. The rHBsAg vaccine was not associated with significant reactogenicity or toxicity and was somewhat more immunogenic than the currently licensed product.

Safety and immunogenicity of Haemophilus influenzae type b polysaccharide and polysaccharide diphtheria toxoid conjugate vaccines in children 15 to 24 months of age.

To evaluate the safety and immunogenicity of the Haemophilus influenzae type b polysaccharide vaccine, PRP, and a new polysaccharide-diphtheria toxoid conjugate vaccine, PRP-D, a collaborative study was carried out in six centers in five states. Subjects were 585 infants 15 to 24 months of age. They were randomly assigned to receive a single dose of PRP or PRP-D vaccine. There were no significant differences in the rate of adverse reactions between the two vaccine groups. Minor local reactions occurred in 10.3% of PRP and 12.5% of PRP-D recipients, and fever in 27.4% of PRP and 23.8% of PRP-D recipients. All reactions resolved within 48 hours. Serum samples were obtained just before vaccination and after 1 month. Prevaccination antibody levels were similar for the PRP (0.035 micrograms/mL) and PRP-D (0.027 micrograms/mL) groups, with no differences in levels by age, sex, race, vaccine lot, or study site. Both groups had significant rises in geometric mean levels, but this difference was significantly greater for PRP-D (2.166 micrograms/mL) than for PRP (0.154 micrograms/mL). In addition, the percentage of responders as determined by three definitions (twofold titer rise, greater than 0.15 micrograms/mL, and greater than 1.0 micrograms/mL) was also significantly greater for PRP-D than PRP. In contrast to a marked age-related immunogenicity to PRP (P less than 0.001), there was no significant variation in immune response to PRP-D by age. PRP-D conjugate vaccine appears to be as safe and significantly more immunogenic than PRP vaccine for children vaccinated at 15 to 24 months of age.

Hepatitis B vaccine: immune responses in children from families with an HBsAg carrier.

A 16 microgram dose of HBsAg prepared by the National Institute of Allergy and Infectious Diseases was administered to 71 children, 18 months to 16 years old. The frequency of seroconversion reached 59% (range: 50-78%) at two weeks following the first dose of vaccine and approached 100% one month after the second dose. There were virtually no side effects. Children less than three years of age developed significantly greater anti-HBs responses than did older children or adults. This appears to be related to the greater dose in microgram kg-1 administered to these children. Anti-HBs responses (mIU ml-1) to the vaccine by the Oriental participants were lower at each sampling interval. Our data suggest that prolonging the third dose of vaccine past six months (e.g. to 12 months) may not significantly alter the eventual antibody levels attained by the vaccinees, but may result in suboptimal protection between the second and third dose in some of them.

Class-specific human bactericidal antibodies to capsular and noncapsular surface antigens of Neisseria meningitidis.

Bactericidal and enzyme-linked immunosorbent assays were used to determine the immunoglobulin classes responsible for group- and type-specific immunity to Neisseria meningitidis among healthy, unvaccinated individuals and persons who received group-B N meningitidis polysaccharide-serotype-2 protein vaccine. Bactericidal antibodies to the group B polysaccharide were primarily IgM; only a few individuals had both IgM and IgG antibodies. IgG bactericidal antibodies were detected only in those individuals with high IgM-antibody levels to group B meningococci. Increased levels of bactericidal antibodies to the group-B polysaccharide were infrequently found in vaccinees, possibly because of high prevaccination bactericidal-antibody levels. Bactericidal antibodies to the group-C polysaccharide were IgM, IgG, or both. Vaccine-induced antibodies to lipopolysaccharide were not bactericidal for a group-C serotype-2 strain with the lipopolysaccharide immunotype of the vaccine strain.

Serum neutralizing antibody and lymphocyte transformation responses after influenza B virus infections.

Serum neutralizing antibody and influenza B-specific lymphocyte blast transformation responses were measured in 110 adults and children after an influenza B outbreak. Serum neutralizing antibody and lymphocyte blast transformation responses were seen in 67 to 75% of adults and children recently infected (less than 1 year), but significant lymphocyte blast transformation responses were seen in only 25% of those whose infection was remote (greater than or equal to 3 years). The frequencies of influenza B-induced lymphocyte blast transformation and serum neutralizing antibody responses were similar in the adults and children with similar infection histories.

Immune responses in serum and respiratory secretions following vaccination with a live cold-recombinant (CR35) and inactivated A/USSR/77 (H1N1) influenza virus vaccine.

One hundred adult volunteers were administered inactivated vaccine (20 micrograms/0.5 cc) intramuscularly (IM) or intranasally (IN), or 10(4.7) TCID50 of a live cold-adapted vaccine (CR35) IN. Microneutralization (Nt) and radioimmunoprecipitation methods were employed to measure hemagglutinin antibody responses in sera, nasal washes, and in bronchopulmonary lavage fluids. In unprimed recipients, the relative frequency of serum antibody response and magnitude of rise was highest following the IM-inactivated vaccine (100%) and lowest after IN-live vaccine (29%). However, in individuals with pre-existing antibody, the three vaccines given were comparably immunogenic. Occurrences of secretory IgA hemagglutinin antibody in nasal washings were more frequently associated with topical administration of live or inactivated vaccine, whereas, IgG hemagglutinin antibody responses occurred with equal frequency in nasal washings in all three vaccine groups. Analysis of the hemagglutinin antibody responses in the lower respiratory tract showed that the IN-live vaccine favored the induction of secretory IgA hemagglutinin antibody and the IM-inactivated vaccine stimulated a more frequent IgG hemagglutinin antibody response.

Influenza immunization in children and young adults: clinical reactions and total and IgM antibody responses after immunization with whole-virus or split-product influenza vaccines.

Clinical reactions and hemagglutinating-inhibiting (HAI) antibody responses to recent whole-virus and split-product influenza vaccines were studied in 168 children and young adults. The subjects initially received a monovalent vaccine, followed one month later by a trivalent preparation. The reactogenicity of whole-virus and split-product vaccines with an equivalent hemagglutinin content was similar except in the youngest age (6 to 36 months) group in which the whole-virus preparation was more reactogenic. The whole-virus vaccines were more immunogenic, especially in subjects who were previously unprimed (preimmunization HAI antibody titer, less than 5). In these subjects, the geometric mean titers of HAI antibody wee significantly higher after vaccination with whole-virus vaccines than the split-product vaccines. Specific IgM antibody was found more frequently after vaccination with whole-virus vaccines (34%) than after split-product vaccines (11%).

Clinical reactions and serologic responses after vaccination with whole-virus or split-virus influenza vaccines in children aged 6 to 36 months.

The reactogenicity and immunogenicity of whole-virus and split-product influenza vaccines were studied in 77 children between the ages of 6 and 36 months. Subjects initially received monovalent vaccine containing either A/USSR/77 (H1N1) antigen in 1978 or A/Brazil/78 (H1N1) antigen in 1979. One month later a trivalent preparation was given which contained the respective H1N1 antigen plus A/Texas/77 (H3N2) and B/Hong Kong/72 antigens. Temperatures of greater than or equal to 37.8 C (greater than or equal to 100 F) were observed more commonly after initial vaccination with whole-virus vaccine (35%) than after split-product vaccine (14%). No child had a temperature of greater than or equal to 39.4 C (103 F) or a febrile convulsion. The trivalent vaccines were more reactogenic than the monovalent vaccines although none of the reaction indices exceeded 0.9. The whole-virus vaccine appeared to be more immunogenic, especially in those children who were initially seronegative (preimmunization hemagglutination-inhibiting antibody titer (less than 5). Only 50% of children vaccinated with split-product vaccines with initial hemagglutination-inhibiting titers of less than 5 achieved titers of greater than or equal to 20 to the H1N1 antigen after two doses of vaccine compared with 97% in similar whole-virus vaccine recipients. The degree of antibody response to the A/Texas/77 component of the vaccines was greater than the response to the A/Brazil/78 or A/USSR/77 antigens.

Adenovirus infection in the immunocompromised patient.

Illness associated adenovirus infection is described in 15 immunocompromised patients. Patients were immunocompromised by severe underlying disease, immunosuppressive or corticosteroid therapy or by age (prematurity). Evidence of adenovirus infection was obtained by either viral isolation or, in two cases, characteristic adenovirus inclusion bodies at postmortem study. All clinical illness was associated with high fever (temperature greater than 39 degrees C). Eighty per cent of the patients had severe systemic complaints including malaise, lethargy, fatigue and night sweats; a similar number of gastrointestinal symptoms. Pulmonary complaints were described in 11 of 15 cases and included cough (67 per cent) and tachypnea (53 per cent). Roentgenologic evidence of pneumonia was demonstrated in 12 of 15 patients (80 per cent). Elevation of serum hepatic enzyme levels (serum glutamic pyruvic transaminase (SGPT)) occurred in eight of 11 patients (73 per cent) and was moderate to severe (serum glutamic pyruvic transaminase greater than 450 IU/liter) in five of 11 (45 per cent). Nine patients died; seven after a rapid downhill course and two after a prolonged illness. Evidence of adenovirus infection microscopically by autopsy in the lung, liver or both is demonstrated in four patients with fulminant systemic illness. Adenovirus infection should be considered in the etiology of severe overwhelming illness in the immunocompromised host.