Efficacy of human rotavirus vaccine against rotavirus gastroenteritis during the first 2 years of life in European infants: randomised, double-blind controlled study.

BACKGROUND: We aimed to assess the efficacy of the oral live attenuated human rotavirus vaccine Rotarix (RIX4414) for prevention of rotavirus gastroenteritis in European infants during their first 2 years of life. METHODS: 3994 study participants were enrolled from six countries and were randomly assigned two oral doses of either RIX4414 (n=2646) or placebo (n=1348), which were coadministered with the first two doses of specific childhood vaccinations. Follow-up for gastroenteritis episodes was undertaken from 2 weeks post-dose two through the two consecutive rotavirus seasons following vaccinations (combined efficacy follow-up period; mean duration 17 months [SD 1.6]). Our primary endpoint was vaccine efficacy against rotavirus gastroenteritis of any severity during the first efficacy follow-up period (2 weeks post-dose two to the end of the first rotavirus season). Stool specimens obtained during gastroenteritis episodes were tested for rotavirus by ELISA and typed by RT-PCR. Episodes scoring 11 or greater on the 20-point Vesikari scale were classified as severe. Analysis was according to protocol. This study is registered with ClinicalTrials.gov, number NCT00140686 (eTrack102247). FINDINGS: 120 infants were excluded from the according-to-protocol analysis. During the first efficacy follow-up period (mean duration 5.7 months [SD 1.2]), 24 of 2572 infants allocated RIX4414 versus 94 of 1302 given placebo had rotavirus gastroenteritis episodes of any severity, resulting in a vaccine efficacy of 87.1% (95% CI 79.6-92.1; p<0.0001). For the combined efficacy follow-up period, vaccine efficacy against severe rotavirus gastroenteritis was 90.4% (85.1-94.1; p<0.0001), for admission owing to rotavirus gastroenteritis 96.0% (83.8-99.5; p<0.0001), and for rotavirus-related medical attention 83.8% (76.8-88.9; p<0.0001), and significant protection against severe rotavirus gastroenteritis by circulating G1, G2, G3, G4, and G9 rotavirus types was shown. INTERPRETATION: In a European setting, two doses of RIX4414 coadministered with childhood vaccines provided high protection against any and severe rotavirus gastroenteritis, with an overall reduction of admissions for gastroenteritis over two consecutive rotavirus epidemic seasons.

Nigerian medical students are at risk for hepatitis B infection.

Medical students are exposed to blood and body fluids. This study was conducted to estimate the prevalence of hepatitis B virus (HBV) infection amongst medical students of the Lagos State University College of Medicine, Ikeja, Nigeria. Data were collected through a self-administered questionnaire and through blood analysis for hepatitis B surface antigen (HBsAg), hepatitis B 'e' antigen (HBeAg) as well as antibodies to the core (anti-HBc), surface (anti-HBs) and 'e' (anti-HBe) antigens. Three hundred and thirteen of 325 students (96%) participated. The mean age was 24.3+/-3.98 years; 231 (74%) were pre-clinical students and 82 (26%) were in the clinical years of study. Only 8 (2.6%) had received three doses of vaccination against HBV. Eighty-one (26%) tested positive for anti-HBc, 10 (3.2%) were positive for HBsAg and 56 (17.9%) had anti-HBs antibodies. A significant relationship was found between students who had a positive history of hepatitis B in the family and anti-HBc (P=0.03). Age was also significantly associated with HBsAg (P=0.012). Two hundred and twenty-five (72%) students were susceptible to the infection and required vaccination. Most students at this medical school are susceptible to HBV infection and should be vaccinated.

Prevalence of hepatitis B surface antigen in vaccinated children and controls in rural Nigeria.

OBJECTIVE: To determine the prevalence of hepatitis B surface antigen (HBsAg) amongst vaccinated children and controls aged 1-4 years in a rural community in mid-western Nigeria. METHODS: The vaccinated children had received at least three doses of hepatitis B vaccine. The vaccines included recombinant hepatitis B vaccine at birth and a combined diphtheria, tetanus, pertussis (whole cell) plus hepatitis B (DTPw-HBV) vaccine. HBsAg was determined by a rapid immunoassay method based on the immunochromatographic sandwich principle. Two hundred and twenty-three children and 219 controls were recruited into the study. RESULTS: The prevalence of HBsAg was significantly lower in the vaccinated group (1.3%) than in the control group (4.6%, p=0.04). The prevalence rates were significantly higher in males (p=0.02) and two-year birth cohort (p=0.01). The controls were estimated to be at a six-fold higher risk of being positive for the surface antigen than the vaccinated children. The vaccine effectiveness was estimated to be approximately 80%. CONCLUSION: These results confirm that hepatitis B vaccine protects against hepatitis B surface antigen carriage and confirm immunogenicity of the combined DTPw-HBV vaccine.

High-dose nifurtimox for arseno-resistant Trypanosoma brucei gambiense sleeping sickness: an open trial in central Zaire.

Thirty patients with arseno-resistant Trypanosoma brucei gambiense sleeping sickness were treated with high-dose nifurtimox (30 mg/kg/d for 30 d). During treatment, the cerebrospinal fluid (CSF) white blood cell (WBC) count decreased in all patients except one (mean CSF WBC count before nifurtimox: 117/mm3; after nifurtimox: 25/mm3), and trypanosomes disappeared from the CSF of all 9 patients in whom parasites had been demonstrated before nifurtimox. Among 25 patients seen at least once after treatment, 9 (36%) have relapsed so far. High-dose nifurtimox was significantly toxic: one patient died during treatment and 8 others developed adverse neurological effects. High-dose nifurtimox seems more effective than the previously used regimen (15 mg/kg/d for 60 d), but at the expense of significant toxicity.

An open clinical trial of nifurtimox for arseno-resistant Trypanosoma brucei gambiense sleeping sickness in central Zaire.

Twenty-five patients with arseno-resistant Trypanosoma brucei gambiense sleeping sickness were treated with oral nifurtimox, 12-17 mg/kg/d for 60 d. During treatment, trypanosomes disappeared from the cerebrospinal fluid (CSF) of 7/7 patients; the CSF infections; leucocyte was significantly lower at the end of treatment than before it was begun (pre-nifurtimox: 124.2 (+/- 149.3) per microliter; post-nifurtimox: 11.9 (+/- 12.1) per microliter; P less than 0.001). Nifurtimox was well tolerated, with gastro-intestinal disturbances in 6 patients and a reversible cerebellar syndrome in 2 patients. Among the 19 patients seen at least once at follow-up, 12 (63%) relapsed. The other 7 patients have been followed for 3-18 months, and the CSF remained completely normal in 4 of them. This study confirms that nifurtimox has some activity against T.b. gambiense, but a daily dosage higher than 15 mg/kg/d will be necessary to achieve cure of most patients.

Short term evaluation of a rural immunization program in Nigeria.

BACKGROUND: Immunization remains the primary strategy in both the control and prevention of common childhood diseases, particularly in the developing world. Immunization and preprimary health care services were commenced in a rural community in Nigeria in 1998, when vaccine coverage for all Expanded Program on Immunization (EPI) diseases (tuberculosis, polio, diphtheria, pertussis, tetanus, measles, and hepatitis B) was considerably low with only 43% of children fully immunized. METHODS: Children aged 0-2 years and living in a rural community were recruited into the study. Data on vaccination history was collected by both vaccination card and maternal history. Three hundred and twenty-seven children were recruited into the study. Study participants were vaccinated for EPI diseases. Hepatitis-B vaccine was administered at birth, and a combined diphtheria and tetanus toxoids, and pertussis whole cell vaccine (DTP) plus hepatitis-B vaccine was administered in a single injection after six weeks. RESULTS AND CONCLUSIONS: Two years after the program was started, immunization coverage rates were 94% for BCG, 88% for DTP (third dose), and 82% for measles. All antigens showed significant improvements from baseline values (p < 0.0001). Eighty four percent of children were fully immunized against all six diseases, compared with 43% at the commencement (p < 0.0001). Hepatitis-B coverage (three doses) was 58%. The vaccination program has significantly improved vaccination coverage and could be a model for under served, non-industrialized communities.

Comparison of the immunogenicity and reactogenicity of two commercially available hexavalent vaccines administered as a primary vaccination course at 2, 4 and 6 months of age.

Infants (N = 459) were randomly assigned to receive either Infanrix hexa or Hexavac vaccines at 2, 4 and 6 months of age as a primary vaccination schedule. The immunogenicity of the hepatitis B component was statistically significantly higher for Infanrix hexa compared to Hexavac in terms of both seroprotection (98.6% versus 94.7%, p = 0.0302) and GMCs (905.6 versus 226.4, p < 0.0001). Significantly (p < or =0.0001) higher antibody levels against diphtheria and the 3 polio components were also induced by Infanrix hexa. The responses to tetanus, Hib and pertussis components were similar. The incidences of clinically relevant solicited symptoms, unsolicited symptoms or serious adverse events were low in both groups.

Specific issues in the design and implementation of an efficacy trial for a Lyme disease vaccine.

Lyme disease is an emerging infection that has now become the most commonly reported vector-borne disease in the United States. In the 20 years since its initial description, scientific and technological advances have led to candidate vaccines for the prevention of Lyme disease. Recombinant outer surface protein A (OspA) vaccines have been successful in protecting mice in tick-challenge experiments. A candidate OspA vaccine has been found to be safe and immunogenic in phase I and II studies. This article describes some of the lessons that were learned and some of the unique obstacles encountered in the design and implementation of a large phase III efficacy field trial. Pivotal trials of vaccines for Lyme disease can be a major investment of time and resources for subjects, investigators, and sponsors. If properly conducted, they also present unique opportunities to expand our knowledge of the disease.

Transmission of vaccine strain varicella-zoster virus from a healthy adult with vaccine-associated rash to susceptible household contacts.

Twelve days after receiving an investigational Oka strain live attenuated varicella vaccine, a 38-year-old healthy white woman developed a rash consisting of 30 scattered lesions. Sixteen days later, her 2 children also developed rash. Swabs obtained from the skin lesions of the vaccinee and her children demonstrated the presence of varicella-zoster virus (VZV) DNA by a polymerase chain reaction (PCR) assay. Restriction endonuclease polymorphisms present in wild and vaccine type VZV were examined, and the amplified VZV DNA was determined to be vaccine type. This case documents transmission of varicella vaccine type virus from a healthy vaccinee to susceptible household contacts. Since vaccine-associated rashes are uncommon and mild, it is likely that transmission of vaccine virus will also be uncommon. With widespread immunization beginning in the United States, ongoing studies will define the frequency of this transmission.

Immunogenicity and safety of a live attenuated varicella vaccine (Oka/SB Bio) in healthy children.

An Oka strain varicella vaccine developed by SmithKline Beecham Biologicals in the early 1980s is registered for immunization of high-risk groups in nine European countries. Because the preparation must be stored at -20 degrees C, it was reformulated to facilitate its use for general vaccination in healthy children with storage at 2-8 degrees C for 2 years. Studies using production lots of the reformulated vaccine in approximately 1400 healthy children are summarized. During the 42-day follow-up, no vaccine-related serious adverse events were reported. Unsolicited reactogenicity rates were low: 14.2% in children ages 9-36 months (the main target age group for the vaccine). Seroconversion rates were 98.6% after a single dose. Consistent reactogenicity and immunogenicity were observed across vaccine lots. After efficacy is demonstrated in other studies, widespread use of this vaccine will prevent a common and potentially serious childhood illness.

Immunogenicity and safety of a live attenuated varicella vaccine in healthy Indian children aged 9-24 months.

OBJECTIVES: To investigate the safety of live attenuated varicella vaccine (Oka strain) and the optimal virus titre/dose required for immunogenicity in healthy South African children. DESIGN: Double-blind randomised clinical study using two different lots of varicella vaccine, each at two different titres. Subjects were randomly allocated to groups 1, 2, 3 and 4 to receive vaccine containing a mean virus titre of 10(4,5), 10(3,1), 10(3,9) and 10(2,7) PFUs per dose respectively. Clinical signs and symptoms were followed up for 42 days post-vaccination. Specific varicella antibodies were measured by an indirect immunofluorescence method in sera obtained on day 0 and day 42. SETTING: City Health Clinic, Chatsworth, Durban. PARTICIPANTS: A total of 200 healthy 9-24-month-old children were vaccinated, of whom 189 (44,5%) completed the study. MAIN OUTCOME MEASURES: Pre- and post-vaccination varicella antibody levels. Adverse events following varicella vaccination. RESULTS: The vaccine was safe and well tolerated. No local symptoms were reported. Skin reactions were specifically solicited in this study: 21 reactions were reported in 8.5% (17/200) of children. Vesicles were reported in 2 vaccines (< or = 10 vesicles in both cases). One serious adverse event was reported: hospitalisation for bronchopneumonia on day 16 post-vaccination which resolved without sequelae. Around day 42 post-vaccination (range 35-63 days) all the 176 initially seronegative subjects had seroconverted for varicella antibodies. Post-vaccination geometric mean titres (GMTs) were 104.1, 66.2, 69.5 and 77.0 for groups 1-4 respectively. Six subjects who were initially seropositive maintained or increased their titres post-vaccination; 3 of the 6 showed a booster response (a > or = 4-fold increase from the pre-vaccination titre). CONCLUSIONS: Varicella vaccine was found to be safe, immunogenic and well tolerated. No difference in seroconversion rates or GMTs, either between groups receiving the two vaccine lots or between groups receiving the different titres of each lot, was shown.

Safety and immunogenicity of an outer surface protein A vaccine in subjects with previous Lyme disease.

The safety and immunogenicity of a recombinant outer surface protein A (OspA) Lyme vaccine in patients previously diagnosed with Lyme disease was assessed in a dose-ranging, prospective study. Thirty healthy volunteers were consecutively assigned to receive three doses of 3, 10, or 30 micrograms of OspA vaccine at 0, 1, and 2 months. Subjects were seen 3 days after each vaccine dose and 1 month after completion of the three-dose schedule. Local side effects included soreness, induration, swelling, and redness. Transient systemic side effects occurred in 21 subjects, the majority of which (81%) were characterized as mild. Solicited symptoms included migratory mild arthralgias that lasted 24 h in 3 subjects. Side effects were not more evident after the second or third dose. Of the patients, 93% developed high-titer OspA antibodies. Thus, an OspA vaccine may be safe and immunogenic in patients with a history of Lyme disease.

A randomised controlled trial with a diphtheria-tetanus-acellular pertussis (dTpa) vaccine in adults.

The aim of this assessor-blinded trial was to compare the immunogenicity and reactogenicity of a candidate diphtheria, tetanus toxoids and acellular pertussis vaccine with reduced antigen content for diphtheria and pertussis (dTpa) with a licensed reduced adult-type diphtheria-tetanus vaccine Td (reduced diphtheria content) and with an experimental candidate monovalent acellular pertussis vaccine with reduced antigen content (pa). The dTpa and pa vaccines had identical pertussis antigen content. A total of 299 healthy adults (> or =18 years, mean age: 30.1 years+/-10.7) were randomised into 3 groups to receive a single dose of one of the study vaccines. In all groups, clinically significant reactions (severe) were infrequent (0-6%) and no serious adverse events were reported during the study. The incidence of local and systemic reactions following the administration of dTpa was comparable to the Td vaccine group. Of the total study group, prior to vaccination 52. 3 and 93.2% of the subjects had anti-diphtheria and anti-tetanus antibody levels > or = 0.1 IU/ml, respectively; and 73.1, 98.2 and 74.5% of the subjects were seropositive for pertussis toxin (PT), filamentous hemagglutinin (FHA) and pertactin (PRN) antibodies, respectively. One month after vaccination, a similar percentage of subjects in the dTpa and Td groups had anti-diphtheria (88.4% vs 90. 1%) and anti-tetanus (100% vs 98.9%) antibody levels > or =0.1 IU/ml. Similar anti-FHA (100%) and anti-PRN (98.9%) vaccine response rates were seen in the dTpa and pa groups, while the anti-PT vaccine response rates were 96.8 and 100.0%, respectively. The dTpa vaccine is as well tolerated and immunogenic as the licensed Td vaccine, and additionally, can also boost antibodies against pertussis.

Use of a reformulated Oka strain varicella vaccine (SmithKline Beecham Biologicals/Oka) in healthy children.

UNLABELLED: The first live-attenuated Oka strain varicella vaccines needed to be stored at -20 degrees C. Reformulation of this vaccine by SmithKline Beecham Biologicals has provided a vaccine shelf life of up to 2 years when stored at +4 degrees C to +8 degrees C. In this study the immunogenicity and reactogenicity of two different production lots of this reformulated vaccine at two different titres each, which corresponded to the release and expected expiry titres, were evaluated. A double-blind randomised clinical trial was conducted in healthy children aged from 9 to 24 months. Immunogenicity was assessed by the measurement of varicella specific antibodies in paired serum samples taken before and from 35 to 63 days post vaccination. Reactogenicity was assessed by the evaluation of any untoward reactions occurring up to 42 days post vaccination. In order to assess protective efficacy, parents of these subjects were contacted approximately 6 months after completion of the trial. One hundred and ninety-one subjects were recruited into the study. Of the 181 initially seronegative subjects who completed the trial according to the protocol, 179 showed seroconversion (98.9%). Reactions to the vaccine were minor and observed in 46/191 (24%) of subjects. Rashes were present in 19, fever in 22, and both fever and rash in 5. Rashes were mainly maculo-papular in nature but were vesicular in 6. Febrile reactions were shortlived. After a 6-month follow up period, attenuated varicella with minor clinical symptoms was diagnosed in 6/52 vaccinees who had close contact with natural varicella (attack rate = 11.5%). CONCLUSION: This reformulated vaccine was well tolerated, highly immunogenic and provided protection against varicella. In increased stability allowing refrigerator storage makes it a good candidate for mass vaccination programmes.

Vaccination against Lyme disease with recombinant Borrelia burgdorferi outer-surface lipoprotein A with adjuvant. Lyme Disease Vaccine Study Group.

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 injection, 16 vaccine recipients and 66 placebo recipients contracted definite Lyme disease (P<0.001); vaccine efficacy was 76 percent (95 percent confidence interval, 58 to 86 percent). The efficacy of the vaccine in preventing asymptomatic infection was 83 percent in the first year and 100 percent in the second year. Injection of the vaccine was associated with mild-to-moderate local or systemic reactions lasting a median of three days. CONCLUSIONS: Three injections of vaccine prevented most definite cases of Lyme disease or asymptomatic B. burgdorferi infection.