Gary B. Calandra

A Controlled Trial of a Formalin-Inactivated Hepatitis A Vaccine in Healthy Children

BACKGROUND Although inactivated hepatitis A vaccine is known to be well tolerated and immunogenic in healthy children and adults, its efficacy has yet to be established. METHODS To evaluate the efficacy of the hepatitis A vaccine in protecting against clinically apparent disease, we conducted a double-blind, placebo-controlled trial in an Hasidic Jewish community in upstate New York that has had recurrent outbreaks of hepatitis A. At the beginning of a summer outbreak, 1037 healthy seronegative children 2 to 16 years of age were randomly assigned to receive one intramuscular injection of a highly purified, formalin-inactivated hepatitis A vaccine or placebo. A case was defined by the presence of typical signs and symptoms, a diagnostic increase in IgM antibody to hepatitis A, and a serum concentration of alanine aminotransferase at least twice the upper limit of normal. Cases occurring greater than or equal to 50 days after the injection were included in the evaluation of efficacy. The children were followed for a mean of 103 days. RESULTS A total of 519 children received vaccine, and 518 received placebo. The vaccine was well tolerated, with no serious adverse reactions. From day 50 after the injection, 25 cases of clinically apparent hepatitis A occurred in the placebo group and none in the vaccine group (P less than 0.001), confirming that the vaccine had 100 percent protective efficacy. Before day 21, seven cases occurred in the vaccine group and three cases in the placebo group. After that time, there were no cases among vaccine recipients and 34 cases among placebo recipients. CONCLUSIONS The inactivated purified hepatitis A vaccine that we tested is well tolerated, and a single dose is highly protective against clinically apparent hepatitis A.

The Efficacy in Navajo Infants of a Conjugate Vaccine Consisting of Haemophilus influenzae Type b Polysaccharide and Neisseria meningitidis Outer-Membrane Protein Complex

BACKGROUND AND METHODS Several conjugate vaccines against Haemophilus influenzae type b have been developed in the search for one that induces protection even in young infants. We evaluated the safety and efficacy of a conjugate vaccine that links the H. influenzae type b capsular polysaccharide to the outer-membrane protein complex (OMPC) of Neisseria meningitidis serogroup B. We conducted a double-blind, placebo, controlled trial in Navajo infants, who are at high risk for systemic infections caused by H. influenzae type b. The infants were randomly assigned to receive the first dose of vaccine or placebo at 42 to 90 days of age and the second at 70 to 146 days of age. RESULTS Of the infants in the trial, 2588 were assigned to receive the vaccine and 2602 to receive placebo. The mean follow-up was 269 days in the vaccine group and 267 days in the placebo group. Before the age of 18 months, there was 1 systemic H. influenzae type b infection in the vaccine group, as compared with 22 in the placebo group (P less than 0.001; point estimate of efficacy, 95 percent; 95 percent confidence interval, 72 to 99 percent). Of the 22 H. influenzae type b infections in the placebo group, 13 were meningitis. Among the children who received both doses, there was 1 H. influenzae type b infection in the vaccine group (n = 2056) and 14 in the placebo group (n = 2105) (P less than 0.001; point estimate of efficacy, 93 percent; 95 percent confidence interval, 53 to 98 percent). The single infection in the vaccine group occurred at 15 1/2 months of age in an infant with osteomyelitis. Between the first and second doses there were no H. influenzae type b infections in the vaccine group and eight in the placebo group (P less than 0.005; point estimate of efficacy, 100 percent; 95 percent confidence interval, 41 to 100 percent). CONCLUSIONS The H. influenzae type b OMPC vaccine, administered at 2 and 4 months of age, is safe and induces a high rate of protection against invasive disease caused by H. influenzae type b in infants under the age of 18 months. Protection begins after the first dose.

Modified cases of chickenpox after varicella vaccination : correlation of protection with antibody response

Four thousand forty-two healthy children and adolescents, ages 12 months to 17 years, were vaccinated with a single dose of live attenuated varicella vaccine (VARIVAX®; Merck Sharp and Dohme Research Laboratories) containing ∼1000 to 1625 plaque-forming units/dose during clinical trials conducted from 1987 to 1989. Clinical follow-up of vaccinees revealed that 2.1 and 2.4% of vaccinees developed modified cases of varicella in the first and second years, respectively, after vaccination. Most of those who developed varicella postvaccination had an attenuated illness, characterized by fewer lesions and a lower incidence of fever (≥100°F, oral) than after natural infection. The likelihood of developing varicella postvaccination decreased (P < 0.0001) as the 6-week postvaccination glycoprotein-based enzyme-linked immunosorbent assay titer increased. In addition the number of lesions in these cases tended to decrease (P = 0.07 for Year 1 and P = 0.02 for Year 2) as the 6-week glycoprotein-based enzyme-linked immunosorbent assay titer increased. Thus the 6-week postvaccination glycoprotein-based enzyme-linked immunosorbent assay titer can be used as a surrogate marker for protection from natural disease.

Factors predisposing to seizures in seriously III infected patients receiving antibiotics: Experience with imipenem/cilastatin

Observations on 1,754 patients treated with imipenem/cilastatin in phase III dose-ranging studies in the United States were reviewed to determine risk factors for seizures. The patients were moderately to severely ill with numerous background disorders known to be associated with an increased risk of seizures. Fifty-two patients (3 percent) had seizures and in 16 (0.9 percent) of them the seizures were judged by the investigators to be possibly, probably, or definitely related to imipenem/cilastatin. An incidence of seizure of 2 to 3 percent was noted among patients treated with other antibiotics (usually including a beta-lactam in the regimen) at times when imipenem/cilastatin was not being given. The average time of onset of seizures for patients receiving imipenem/cilastatin was seven days after start of therapy. As with other beta-lactam antibiotics, central nervous system lesions and disorders including seizures and renal insufficiency were found to be strong risk factors for seizures. Imipenem/cilastatin dosages in excess of those currently recommended by the manufacturer, particularly in patients with renal insufficiency, were also associated with an increased risk of seizures. There was an association with Pseudomonas aeruginosa infection that remained statistically significant even after controlling for imipenem/cilastatin dosage as well as for the other factors indicated. A high background incidence of seizures in general in a group of severely ill patients makes it both difficult to assess the etiology of a seizure and important to consider the risk factors when choosing the appropriate dose of an antibiotic. Guidelines are presented for appropriate dosing of imipenem/cilastatin in relation to renal function, body weight, and infecting pathogen.

Review of adverse experiences and tolerability in the first 2,516 patients treated with imipenem/cilastatin

The clinical and laboratory data relating to the adverse experiences and tolerability of imipenem/cilastatin in the first 2,516 patients treated with the antibiotic are reviewed, with special reference to the last 793. Clinical adverse experiences were predominantly related to the gastrointestinal system (nausea and vomiting), local injection site, and allergy (rash). A low frequency of drug-related seizures was also reported. The most frequent adverse laboratory experiences were transient elevations of liver function test values. In general, the safety profile was similar to that of other beta-lactam antibiotics.

The Efficacy Results and Safety Profile of Imipenem/Cilastatin from the Clinical Research Trials

Imipenem/cilastatin is highly effective for infections in many body sites against a broad range of gram‐positive and gram‐negative aerobic and anaerobic bacteria. During therapy, development of resistance is uncommon except in the case of Pseudomonas aeruginosa in which the incidence appears similar to that for other beta‐lactam antibiotics. There appears to be a very low probability of cross‐resistance. The clinical and laboratory adverse reactions are similar in type to those for other beta‐lactam antibiotics. The frequency of colonization and superinfection during treatment with imipenem/cilastatin has been comparable to other antibiotics in comparative trials and to literature reports for other antibiotics for noncomparative trials.

Antibody responses of healthy infants to a recombinant hepatitis B vaccine administered at two, four, and twelve or fifteen months of age

Hepatitis B vaccine was administered to healthy infants on two investigational schedules that fall within ranges recommended by the U.S. Public Health Service Advisory Committee on Immunization Practices and by the American Academy of Pediatrics Committee on Infectious Diseases. A month after receiving vaccine at 2, 4, and 12 or 15 months of age, 98% and 100% of the children had > 10 mIU antibodies to hepatitis B surface antigen per milliliter, with gemometric mean titers of 1358 mIU/ml and 3424 mIU/mL, respectively.

Safety profile and immunogenicity of an inactivated vaccine derived from an attenuated strain of hepatitis A.

To determine the safety and immunogenicity of an inactivated hepatitis A vaccine, 56 healthy adult volunteers were randomly assigned to receive an intramuscular injection of 6.3, 12.5 or 25 ng of inactivated hepatitis A vaccine or placebo at 0, 2 or 4, and 24 weeks. Adverse reactions occurred with similar frequency in vaccine and placebo recipients and consisted primarily of pain or tenderness at the injection site. By 4 weeks after a single 6.3, 12.5 or 25 ng injection, seven, nine and ten out of ten vaccinees, respectively, had antibody detectable by a HAV AB assay modified to increase its sensitivity tenfold. All vaccinees had antibodies detectable by this assay within 2 weeks of their second inoculation. Geometric mean antibody levels increased with higher doses of vaccine (p = 0.05). Neutralizing antibody was detected within 4 weeks of a single inoculation in all vaccinees. Neutralizing antibody was detected after the third inoculation at dilutions of greater than or equal to 1:2048 in all 12.5 and 25 ng vaccinees. All 19 vaccinees tested at 24 months still had HAV antibodies detectable by a modified HAV AB assay. This inactivated hepatitis A vaccine appears to be well tolerated and immunogenic at doses of 6.3-25 ng. The choice of dose and vaccination schedule may depend on the rapidity with which seroconversion is desired.

Comparative safety and immunogenicity of yeast recombinant hepatitis B vaccines containing S and pre-S2+S antigens

One hundred and four healthy, hepatitis B virus (HBV) seronegative males were enrolled in a single blind, randomized pilot study to compare antibody and clinical responses to a yeast recombinant pre-S2 + S vaccine and a yeast recombinant S antigen vaccine (Recombivax HBR). Participants received either a 12, 24 or 48 micrograms dose of pre-S2 + S vaccine (with a 1:5 ratio by weight of pre-S2 and S antigens) or a 10 micrograms dose of Recombivax HBR by intramuscular injection at 0, 1 and 6 months; their serological and biochemical responses were measured at 0, 1, 2, 3, 6 and 7 months, while their clinical responses were monitored for 5 days after each injection. The proportion of vaccines with minor local or systemic complaints (mainly sore arm, malaise, myalgia, fatigue) and the proportion developing antibody to surface antigen (anti-HBs) were similar for all vaccine groups. Transient elevations in alanine aminotransferase occurred infrequently. By 7 months almost all vaccinees developed anti-HBs, but titres were generally higher among recipients of pre-S2 + S vaccine. Antibody to pre-S2 antigen developed in 70-75% by 2 months and in 91-96% by 7 months. These data imply that the recombinant yeast pre-S2 + S vaccine is as well tolerated and as immunogenic as Recombivax HBR. Further studies are being conducted to assess antibody responses in larger numbers of healthy adults as well as in special populations with sub-optimal responses to currently licensed hepatitis B vaccines.

Clinical experience with PedvaxHIB, a conjugate vaccine of Haemophilus influenzae type b polysaccharide—Neisseria meningitidis outer membrane protein

PedvaxHIB, a Haemophilus influenzae type b (Hib) conjugate vaccine composed of Hib capsular polysaccharide covalently bound to an outer membrane protein complex of Neisseria meningitidis serogroup B, was evaluated for immunogenicity and safety in infants and children 2 months of age and older. A significant and consistent antibody response was seen after a single dose of the vaccine in all age groups, including infants as young as 2 months of age. In addition, the vaccine elicited a good booster response when given at 12 to 17 months of age. Subjects from diverse subpopulations, including those with impaired antibody response to Hib polysaccharide vaccines, showed a significant response to vaccination. The vaccine was well tolerated when administered alone or concurrently with other paediatric vaccines. A protective efficacy study, recently completed, has shown the vaccine to be highly effective in 2-month-old infants.