Edward P. Rothstein

Efficacy of live, attenuated, human rotavirus vaccine 89-12 in infants : a randomised placebo-controlled trial

BACKGROUND Rotavirus is the most common cause of severe, dehydrating diarrhoea in infants worldwide. We assessed the safety, immunogenicity, and efficacy of a live, oral human rotavirus vaccine, 89-12, in US children in a randomised, placebo-controlled, double-blind multicentre trial. METHODS 215 healthy infants were enrolled, of whom 213 were given two doses of 89-12 (containing 1x10(5) plaque-forming units) or placebo, and 213 were followed up through one rotavirus season. The frequency of side-effects was compared for 7 days after each dose of vaccine. Immune responses to rotavirus were assessed by serum and stool IgA, and by serum 89-12 neutralising titres. The primary outcome variable (protection from rotavirus disease) was evaluated by comparing the frequencies of rotavirus gastroenteritis in an intention-to-treat analysis. FINDINGS Adverse reactions were mild. Low-grade fever (> or = 38.1 degrees C) after the first dose was the only side-effect significantly more common in the vaccine group than in the placebo group (21 [19%] vs 5 [5%], p=0.001). An immune response to vaccine was detected in 94.4% of vaccinees. Rotavirus disease occurred in 18 of 107 placebo recipients and two of 108 vaccine recipients (vaccine efficacy 89.0% [95% CI 65.4-94.5]). Ten infants in the placebo group but none in the vaccine group were presented for medical care. INTERPRETATION The 89-12 rotavirus vaccine was safe and immunogenic and provided a high degree of protection against rotavirus disease. Further investigations of this vaccine are needed to confirm these findings in other settings.

Comparative trial of the safety and immunogenicity of quadrivalent (A, C, Y, W-135) meningococcal polysaccharide-diphtheria conjugate vaccine versus quadrivalent polysaccharide vaccine in two- to ten-year-old children.

Background: A quadrivalent meningococcal diphtheria conjugate vaccine (MCV-4) has been developed to provide T-cell dependent immune responses against 4 major disease-causing serogroups (A, C, Y, W-135). Methods: In a comparative, randomized, modified double blind, controlled study in healthy 2- to 10-year-old U.S. children, safety and immunogenicity profiles of MCV-4 (n = 696) were compared with those of a licensed quadrivalent polysaccharide vaccine, Menomune A/C/Y/W-135 (PSV-4, n = 702). Vaccine-related adverse reactions were assessed for 28-day and 6-month follow-up periods. Serum bactericidal activity (SBA) was assayed in prevaccination, day 28 and 6-month postvaccination sera samples. Results: Both vaccines were well-tolerated, with no vaccine-related serious adverse events and similar rates of mostly mild local and systemic reactions. Functional antibody (SBA) seroconversion percentages were significantly higher for all 4 serogroups in the MCV-4 group. The SBA geometric mean titers against serogroups A, C, Y and W-135 with MCV-4 were 1700, 354, 637 and 750, respectively, compared with PSV-4 (893, 231, 408 and 426) 28 days postvaccination (P < 0.001 for all comparisons). This significant difference persisted through 6 months. Conclusions: In 2- to 10-year-old children MCV-4 had a safety profile similar to that of PSV-4 and elicited significantly higher and more persistent serum bactericidal antibody responses against meningococcal serogroups A, C, Y and W-135 than did the licensed polysaccharide vaccine.

Infant Immunization with Pneumococcal CRM197 Vaccines: Effect of Saccharide Size on Immunogenicity and Interactions with Simultaneously Administered Vaccines

Six pentavalent pneumococcal conjugate vaccines (Pn-CRM197) were evaluated among 400 infants. The vaccines differed in saccharide chain length (oligosaccharide [OS] or polysaccharide [PS]) and saccharide quantity (0.5, 2, or 5 microg). Subjects were randomized into groups 1-6 (Pn-CRM197 recipients) or 7 (controls) for immunization at 2, 4, and 6 months of age. Pn-CRM197 were well tolerated and elicited mean antibody concentrations that exceeded those in controls for all 5 capsular serotypes. PS formulations were generally more immunogenic than their OS counterparts. For PS vaccines, a dose-response was documented (5 microg > 2 microg > 0.5 microg), but the differences between the 5- and 2-microg formulations were insignificant. The mean anti-PRP antibody concentration was significantly higher among Pn-CRM197 recipients. It is concluded that PS vaccines are more immunogenic than OS vaccines. The improved immunogenicity from Haemophilus type b oligosaccharide conjugate (HbOC) vaccine when given with Pn-CRM197 suggests that a decreased dose of HbOC vaccine may be sufficient to elicit protection.

Health burden of pertussis in adolescents and adults

Pertussis in adolescents and adults is common, endemic, and epidemic worldwide, and its incidence is reportedly increasing. Although a number of individuals suffer only a mild cough, many others have symptoms typical of pertussis, causing prolonged cough illness, frequent use of health care resources, missed work and a variety of complications. Symptoms experienced by adolescents and adults include sleep disturbance, weight loss, pharyngeal discomfort, influenza-like symptoms, sneezing attacks, hoarseness, sinus pain, headaches and sweating attacks. Even when symptoms are typical of pertussis, the diagnosis is often not considered in adolescents and adults because of a low awareness of the disease in these age groups. Contrary to common perceptions, complications of pertussis, including some that are serious, are not infrequent in adolescents and adults. These include urinary incontinence, rib fracture, pneumothorax, inguinal hernia, aspiration, pneumonia, seizures and otitis media. Despite underreporting, hospitalization of adults and adolescents does occur. Many believe that adolescents and adults are the groups most commonly infected with pertussis and are now the major source of contagion to infants and young children. Because of the considerable health burden, there is a need for improved vaccination strategies to prevent disease in adolescents and adults and to reduce the risk of transmission to vulnerable infants.

Second-Year Follow-up Evaluation of Live, Attenuated Human Rotavirus Vaccine 89-12 in Healthy Infants

Rotavirus vaccine development is a high priority. The association between the tetravalent rhesus-human reassortant rotavirus vaccine and intussusception has increased the need to develop new vaccines. In a small efficacy trial, the human rotavirus vaccine 89-12 recently has been shown to be safe and effective; 184 of the 215 healthy infants initially enrolled in this trial were followed for a second year. Vaccine efficacy during the second year was 59% (P=.047). For the 2 years of observation, vaccine efficacy was 76% against rotavirus gastroenteritis, 83% against severe rotavirus gastroenteritis, and 100% against rotavirus illnesses requiring medical intervention (P<.001 for each). These encouraging results have led to continued evaluation, in several countries, of a vaccine candidate derived from strain 89-12.

A local reaction at or near injection site: Case definition and guidelines for collection, analysis, and presentation of immunization safety data

The need for developing a case definition and guidelines for a local reaction at or near the injection site, methods for the development of the case definition and guidelines as an adverse event following immunization as well as the rationale for selected decisions about the case definition for a local reaction at or near the injection site are explained in the Preamble section. The case definition is structured in 2 levels of diagnostic certainty: level 1 includes any description of morphological or physiological change at or near the injection site that is described or identified by a healthcare provider. Level 2 is any description of morphological or physiological change at or near injection site that is described by any other person. In Guidelines section, the working group recommends to enable meaningful and standardized data collection, analysis, and presentation of information about a local reaction at or near the injection site. However, implementation of all guidelines might not be possible in all settings. The availability of information may vary depending upon resources, geographic region, and whether the source of information is a prospectively designed clinical trial, a post-marketing surveillance or epidemiologic study, or an individual report of a local reaction at injection site.

Pertussis immunization in the Global Pertussis Initiative North American Region: Recommended strategies and implementation considerations

In North America, children currently receive 5 doses of a combined diphtheria-tetanus-acellular pertussis vaccine between the ages of 2 months and 6 years. Although this schedule has reduced the incidence of childhood pertussis, it has not led to the development of herd immunity in the total population, largely because pertussis immunity wanes with time. The time course over which immunity wanes is uncertain; however, high pertussis antibody titers in adolescents and adults indicate unrecognized infection in these groups. There is evidence that this group serves as a source of infection for young infants who are not fully immunized. Therefore, of the potential strategies reviewed by the North American Global Pertussis Initiative group, universal adolescent immunization would in theory reduce the risk of pertussis in this age group and may reduce transmission to young infants. However, because immunity probably wanes at the same rate in adolescents and children, the burden of disease will likely shift to older age groups, including young adults (parents of vulnerable infants). Therefore the ideal would be immunization of adolescents and adults, particularly those who are in contact with young infants. Adolescent immunization is already recommended in Austria, France, Germany and Canada, and participants in the Global Pertussis Initiative recommend that this strategy be implemented across North America with a view to eventually extending immunization to ínclude adults. The final decision to implement such a strategy will depend on pertussis surveillance studies and analysis of the effectiveness and tolerability of adolescent and adult pertussis immunization as well as program considerations related to feasiblity and economics.

Safety and immunogenicity of a measles, mumps, rubella and varicella vaccine given with combined Haemophilus influenzae type b conjugate/hepatitis B vaccines and combined diphtheria-tetanus-acellular pertussis vaccines.

Background: A study was conducted to assess administration of a combination measles, mumps, rubella and varicella vaccine (MMRV) with other childhood vaccines. Methods: In this open, multicenter trial, 1915 healthy children ages 12–15 months were randomized into 3 groups: group 1, MMRV, combined Haemophilus influenzae type b conjugate-hepatitis B vaccines (Hib/HepB) and combined diphtheria-tetanus-acellular pertussis vaccines (DTaP) concomitantly; group 2, MMRV followed by Hib/HepB and DTaP 42 days later; group 3, MMR and varicella vaccine followed by Hib/HepB and DTaP 42 days later. Results: Antibody responses to measles, mumps, rubella, varicella, Hib, HepB, diphtheria and tetanus were similar between groups 1 and 2 (all >95%, except varicella, 89.7% in group 1 and 90.9% in group 2). Pertussis toxin and filamentous hemagglutinin responses were significantly lower in group 1 than in group 2 (group 1, 74.1 and 67.1%; group 2, 90.4 and 86.8%, respectively). An exploratory analysis suggested that the difference in and pertussis toxin and filamentous hemagglutinin responses was likely the result of study design rather than interference among vaccine components because the groups differed in age of receipt of DTaP (group 1, ∼12 months; group 2, ∼13.5 months). When the groups were matched for age, sample size was sufficient for comparison only in children ≥13.5 months old. Pertussis toxin and filamentous hemagglutinin responses were similar in these children. The safety profiles for each vaccination regimen were comparable. Conclusions: The immunogenicity data support concomitant administration of MMRV with Hib/HepB. Limited data from an exploratory analysis indicate that MMRV can be administered concomitantly with DTaP. Concomitant administration of MMRV, Hib/HepB and DTaP is well-tolerated.

Reactogenicity and immunogenicity of a three-component acellular pertussis vaccine administered as the primary series to 2, 4 and 6 month old infants in the United States

Five hundred and fifty-seven infants received either an acellular pertussis (DTaP) vaccine containing pertussis toxoid (PT), filamentous hemagglutinin (FHA) and pertactin (PRN) or one of two commercially available whole-cell pertussis (DTP) vaccines at 2, 4 and 6 months. One month after the third immunization, IgG antibody values to pertussis toxoid, filamentous hemagglutinin and PRN were significantly greater following DTaP than either DTP (P < 0.05). When reactions within 48 h after all three doses of vaccine were combined, fever 101 degrees, > or = moderate fussiness, > or = moderate pain, swelling 10 mm, and erythema 10 mm occurred less often after DTaP compared with DTP-Connaught (P < 0.001). The same adverse events were also less after DTaP compared with DTP-Lederle (P < 0.05), except for erythema 10 mm. This three-component DTaP vaccine produced fewer adverse events and greater antibody values to PT, FHA and PRN in comparison with either licensed DTP vaccine when given as the primary series.

An acellular pertussis vaccine in healthy adults: safety and immunogenicity

Recent data indicate that Bordetella pertussis can be an important cause of illness in adolescents and adults. In a randomized observer- and subject-blinded study, adults (> or = 18 years of age) received an acellular pertussis (aP) vaccine containing genetically inactivated pertussis toxin (PT), filamentous hemagglutinin (FHA) and pertactin (PRN), or a saline placebo, and were monitored for safety and immunogenicity. IgG antibodies to PT, FHA, and PRN were measured by enzyme-linked immunosorbent assay (ELISA) and PT neutralization by a Chinese hamster ovary (CHO) cell assay. Local reactions, more common in the aP group, were mild and transient. One month after immunization, geometric mean ELISA antibody concentrations for the aP and placebo groups, respectively, were: anti-PT, 463 and 7.6; anti-FHA, 417 and 18; and anti-PRN, 855 and 14. The anti-PT neutralization titers for the aP and placebo groups were 1:3439 and 1:58 respectively. This aP vaccine is a safe and immunogenic candidate booster vaccine against pertussis for adults.