Anthony Burton

2008 estimate of worldwide rotavirus-associated mortality in children younger than 5 years before the introduction of universal rotavirus vaccination programmes: a systematic review and meta-analysis

BACKGROUND WHO recommends routine use of rotavirus vaccines in all countries, particularly in those with high mortality attributable to diarrhoeal diseases. To establish the burden of life-threatening rotavirus disease before the introduction of a rotavirus vaccine, we aimed to update the estimated number of deaths worldwide in children younger than 5 years due to diarrhoea attributable to rotavirus infection. METHODS We used PubMed to identify studies of at least 100 children younger than 5 years who had been admitted to hospital with diarrhoea. Additionally, we required the studies to have a data collection midpoint of the year 2000 or later, to be done in full-year increments, and to assesses diarrhoea attributable to rotavirus with EIAs or polyacrylamide gel electrophoresis. We also included data from countries that participated in the WHO-coordinated Global Rotavirus Surveillance Network (consisting of participating member states during 2009) and that met study criteria. For countries that have introduced a rotavirus vaccine into their national immunisation programmes, we excluded data subsequent to the introduction. We classified studies into one of five groups on the basis of region and the level of child mortality in the country in which the study was done. For each group, to obtain estimates of rotavirus-associated mortality, we multiplied the random-effect mean rotavirus detection rate by the 2008 diarrhoea-related mortality figures for countries in that group. We derived the worldwide mortality estimate by summing our regional estimates. FINDINGS Worldwide in 2008, diarrhoea attributable to rotavirus infection resulted in 453,000 deaths (95% CI 420,000-494,000) in children younger than 5 years-37% of deaths attributable to diarrhoea and 5% of all deaths in children younger than 5 years. Five countries accounted for more than half of all deaths attributable to rotavirus infection: Democratic Republic of the Congo, Ethiopia, India, Nigeria, and Pakistan; India alone accounted for 22% of deaths (98,621 deaths). INTERPRETATION Introduction of effective and available rotavirus vaccines could substantially affect worldwide deaths attributable to diarrhoea. Our new estimates can be used to advocate for rotavirus vaccine introduction and to monitor the effect of vaccination on mortality once introduced.

Global Mortality Associated with Rotavirus Disease among Children in 2004

BACKGROUND As new rotavirus vaccines are being introduced in immunization programs, global and national estimates of disease burden, especially rotavirus-associated mortality, are needed to assess the potential health benefits of vaccination and to monitor vaccine impact. METHODS We identified 76 studies that were initiated after 1990, lasted at least 1 full year, and examined rotavirus among >100 children hospitalized with diarrhea. The studies were assigned to 5 groups (A-E) with use of World Health Organization classification of countries by child mortality and geography. For each group, the mean rotavirus detection rate was multiplied by diarrhea-related mortality figures from 2004 for countries in that group to yield estimates of rotavirus-associated mortality. RESULTS Overall, rotavirus accounted for 527,000 deaths (95% confidence interval, 475,000-580,000 deaths) annually or 29% of all deaths due to diarrhea among children <5 years of age. Twenty-three percent of deaths due to rotavirus disease occurred in India, and 6 countries (India, Nigeria, Congo, Ethiopia, China, and Pakistan) accounted for more than one-half of deaths due to rotavirus disease. CONCLUSIONS The high mortality associated with rotavirus disease underscores the need for targeted interventions, such as vaccines. To realize the full life-saving potential of vaccines, it will be vital to ensure that they reach children in countries with high mortality. These baseline figures will allow future assessment of vaccine impact on rotavirus-associated mortality.

Assessment of the 2010 global measles mortality reduction goal: results from a model of surveillance data

BACKGROUND In 2008 all WHO member states endorsed a target of 90% reduction in measles mortality by 2010 over 2000 levels. We developed a model to estimate progress made towards this goal. METHODS We constructed a state-space model with population and immunisation coverage estimates and reported surveillance data to estimate annual national measles cases, distributed across age classes. We estimated deaths by applying age-specific and country-specific case-fatality ratios to estimated cases in each age-country class. FINDINGS Estimated global measles mortality decreased 74% from 535,300 deaths (95% CI 347,200-976,400) in 2000 to 139,300 (71,200-447,800) in 2010. Measles mortality was reduced by more than three-quarters in all WHO regions except the WHO southeast Asia region. India accounted for 47% of estimated measles mortality in 2010, and the WHO African region accounted for 36%. INTERPRETATION Despite rapid progress in measles control from 2000 to 2007, delayed implementation of accelerated disease control in India and continued outbreaks in Africa stalled momentum towards the 2010 global measles mortality reduction goal. Intensified control measures and renewed political and financial commitment are needed to achieve mortality reduction targets and lay the foundation for future global eradication of measles. FUNDING US Centers for Disease Control and Prevention (PMS 5U66/IP000161).

WHO and UNICEF estimates of national infant immunization coverage: methods and processes

WHO and the United Nations Childrens Fund (UNICEF) annually review data on immunization coverage to estimate national coverage with routine service delivery of the following vaccines: bacille Calmette-Guérin; diphtheria-tetanus-pertussis, first and third doses; either oral polio vaccine or inactivated polio vaccine, third dose of either; hepatitis B, third dose; Haemophilus influenzae type b, third dose; and a measles virus-containing vaccine, either for measles alone or in the form of a combination vaccine, one dose. The estimates are based on government reports submitted to WHO and UNICEF and are supplemented by survey results from the published and grey literature. Local experts, primarily national immunization system managers and WHO/UNICEF regional and national staff, are consulted for additional information on the performance of specific immunization systems. Estimates are derived through a country-by-country review of available data informed and constrained by a set of heuristics; no statistical or mathematical models are used. Draft estimates are made, sent to national authorities for review and comment and modified in light of their feedback. While the final estimates may not differ from reported data, they constitute an independent technical assessment by WHO and UNICEF of the performance of national immunization systems. These country-specific estimates, available from 1980 onward, are updated annually.

Hepatitis B virus infection among children born in the United States to Southeast Asian refugees

Abstract Since 1975 nearly 1 million persons have entered the United States from Southeast Asia, where infection with hepatitis B virus (HBV) is hyperendemic. To evaluate the prevalence and patterns of transmission of HBV infection among the children of refugees from Southeast Asia, we studied 196 refugee families with 257 children born in the United States. Of 31 children born in the United States to mothers with infectious disease, 17 (55 percent) had been infected with HBV. Of 226 children whose mothers did not have infectious disease, 15 had HBV infection — a prevalence of 6.6 percent (95 percent confidence interval, 4.1 to 10.7). The risk of infection was greatest (26 percent) among children living in households with children with infectious disease (relative risk, 5.5; confidence interval, 2.3 to 13.4). Exposure to fathers or other adults with infectious disease was not significantly associated with infection. Of children from households with no persons with infectious disease, 3.9 percent (confiden...

Fractional doses of inactivated poliovirus vaccine in Oman.

BACKGROUND We conducted a clinical trial of fractional doses of inactivated poliovirus vaccine administered to infants in Oman, in order to evaluate strategies for making the vaccine affordable for use in developing countries. METHODS We compared fractional doses of inactivated poliovirus vaccine (0.1 ml, representing one fifth of a full dose) given intradermally with the use of a needle-free jet injector device, with full doses of vaccine given intramuscularly, with respect to immunogenicity and reactogenicity. Infants were randomly assigned at birth to receive either a fractional dose or a full dose of inactivated poliovirus vaccine at 2, 4, and 6 months. We also administered a challenge dose of monovalent type 1 oral poliovirus vaccine at 7 months and collected stool samples before and 7 days after administration of the challenge dose. RESULTS A total of 400 infants were randomized, of whom 373 (93.2%) fulfilled the study requirements. No significant baseline differences between the groups were detected. Thirty days after completion of the three-dose schedule, the rates of seroconversion to types 1, 2, and 3 poliovirus were 97.3%, 95.7%, and 97.9%, respectively, in the fractional-dose group, as compared with 100% seroconversion to all serotypes in the full-dose group (P=0.01 for the comparison with respect to type 2 poliovirus; results with respect to types 1 and 3 poliovirus were not significant). The median titers were significantly lower in the fractional-dose group than in the full-dose group (P<0.001 for all three poliovirus serotypes). At 7 months, 74.8% of the infants in the fractional-dose group and 63.1% of those in full-dose group excreted type 1 poliovirus (P=0.03). Between birth and 7 months, 42 hospitalizations were reported, all related to infectious causes, anemia, or falls, with no significant difference between vaccination groups. CONCLUSIONS These data show that fractional doses of inactivated poliovirus vaccine administered intradermally at 2, 4, and 6 months, as compared with full doses of inactivated poliovirus vaccine given intramuscularly on the same schedule, induce similar levels of seroconversion but significantly lower titers. (Current Controlled Trials number, ISRCTN17418767.)

Immunogenicity of bivalent types 1 and 3 oral poliovirus vaccine: a randomised, double-blind, controlled trial

BACKGROUND Poliovirus types 1 and 3 co-circulate in poliomyelitis-endemic countries. We aimed to assess the immunogenicity of a novel bivalent types 1 and 3 oral poliovirus vaccine (bOPV). METHODS We did a randomised, double-blind, controlled trial to assess the superiority of monovalent type 2 OPV (mOPV2), mOPV3, or bOPV over trivalent OPV (tOPV), and the non-inferiority of bivalent vaccine compared with mOPV1 and mOPV3. The study was done at three centres in India between Aug 6, 2008, and Dec 26, 2008. Random allocation was done by permuted blocks of ten. The primary outcome was seroconversion after one monovalent or bivalent vaccine dose compared with a dose of trivalent vaccine at birth. The secondary endpoints were seroconversion after two vaccine doses compared with after two trivalent vaccine doses and cumulative two-dose seroconversion. Parents or guardians and study investigators were masked to treatment allocation. Because of multiple comparisons, we defined p≤0·01 as statistically significant. This trial is registered with Current Controlled Trials, ISRCTN 64725429. RESULTS 900 newborn babies were randomly assigned to one of five vaccine groups (about 180 patients per group); of these 70 (8%) discontinued, leaving 830 (92%) for analysis. After the first dose, seroconversion to poliovirus type 1 was 20% for both mOPV1 (33 of 168) and bOPV (32 of 159) compared with 15% for tOPV (25 of 168; p>0·01), to poliovirus type 2 was 21% (35 of 170) for mOPV2 compared with 25% (42 of 168) for tOPV (p>0·01), and to poliovirus type 3 was 12% (20 of 165) for mOPV3 and 7% (11 of 159) for bOPV compared with 4% (7 of 168) for tOPV (mOPV3 vs tOPV p=0·01; bOPV vs tOPV; p>0·01). Cumulative two-dose seroconversion to poliovirus type 1 was 90% (151 of 168) for mOPV1 and 86% (136 of 159) for bOPV compared with 63% (106 of 168) for tOPV (p<0·0001), to poliovirus type 2 was 90% (153 of 170) for mOPV2 compared with 91% (153 of 168) for tOPV (p>0·01), and to poliovirus type 3 was 84% (138 of 165) for mOPV3 and 74% (117 of 159) for bOPV compared with 52% (87 of 168) for tOPV (p<0·0001). The vaccines were well tolerated. 19 serious adverse events occurred, including one death; however, these events were not attributed to the trial interventions. INTERPRETATION The findings show the superiority of bOPV compared with tOPV, and the non-inferiority of bOPV compared with mOPV1 and mOPV3. FUNDING GAVI Alliance, World Health Organization, and Panacea Biotec.

Randomized Controlled Clinical Trial of Fractional Doses of Inactivated Poliovirus Vaccine Administered Intradermally by Needle-Free Device in Cuba

BACKGROUND As part of an evaluation of strategies to make inactivated poliovirus vaccine (IPV) affordable for developing countries, we conducted a clinical trial of fractional doses of IPV in Cuba. METHODS We compared the immunogenicity and reactogenicity of fractional-dose IPV (0.1 mL, or 1/5 of a full dose) given intradermally using a needle-free jet injector device compared with full doses given intramuscularly. Subjects were randomized at birth to receive IPV at 6, 10, and 14 weeks. RESULTS A total of 471 subjects were randomized to the 2 study groups, and 364 subjects fulfilled the study requirements. No significant differences at baseline were detected. Thirty days after completing the 3-dose schedule of IPV, 52.9%, 85.0%, and 69.0% of subjects in the fractional-dose IPV arm seroconverted for poliovirus types 1, 2, and 3, respectively, whereas 89.3%, 95.5%, and 98.9% of subjects in the full-dose IPV arm seroconverted for poliovirus types 1, 2, and 3, respectively (all comparisons, P < .001). The median titers of each poliovirus serotype were significantly lower in the intradermal arm than in the intramuscular arm (P < .001). Only minor local adverse effects and no moderate or serious adverse events were reported. CONCLUSIONS This large-scale evaluation demonstrates the feasibility of fractional doses of IPV given intradermally as an antigen-sparing strategy but also shows that IPV given to infants at 6, 10, and 14 weeks of age results in suboptimal immunogenicity (especially for the fractional-dose arm).

Priming after a Fractional Dose of Inactivated Poliovirus Vaccine

BACKGROUND To reduce the costs of maintaining a poliovirus immunization base in low-income areas, we assessed the extent of priming immune responses after the administration of inactivated poliovirus vaccine (IPV). METHODS We compared the immunogenicity and reactogenicity of a fractional dose of IPV (one fifth of a full dose) administered intradermally with a full dose administered intramuscularly in Cuban infants at the ages of 4 and 8 months. Blood was collected from infants at the ages of 4 months, 8 months, 8 months 7 days, and 8 months 30 days to assess single-dose seroconversion, single-dose priming of immune responses, and two-dose seroconversion. Specimens were tested with a neutralization assay. RESULTS A total of 320 infants underwent randomization, and 310 infants (96.9%) fulfilled the study requirements. In the group receiving the first fractional dose of IPV, seroconversion to poliovirus types 1, 2, and 3 occurred in 16.6%, 47.1%, and 14.7% of participants, respectively, as compared with 46.6%, 62.8%, and 32.0% in the group receiving the first full dose of IPV (P<0.008 for all comparisons). A priming immune response to poliovirus types 1, 2, and 3 occurred in 90.8%, 94.0%, and 89.6% of participants, respectively, in the group receiving the fractional dose as compared with 97.6%, 98.3%, and 98.1% in the group receiving the full dose (P=0.01 for the comparison with type 3). After the administration of the second dose of IPV in the group receiving fractional doses, cumulative two-dose seroconversion to poliovirus types 1, 2, and 3 occurred in 93.6%, 98.1%, and 93.0% of participants, respectively, as compared with 100.0%, 100.0%, and 99.4% in the group receiving the full dose (P<0.006 for the comparisons of types 1 and 3). The group receiving intradermal injections had the greatest number of adverse events, most of which were minor in intensity and none of which had serious consequences. CONCLUSIONS This evaluation shows that vaccinating infants with a single fractional dose of IPV can induce priming and seroconversion in more than 90% of immunized infants. (Funded by the World Health Organization and the Pan American Health Organization; Australian New Zealand Clinical Trials Registry number, ACTRN12610001046099.).

Immunogenicity of supplemental doses of poliovirus vaccine for children aged 6-9 months in Moradabad, India: a community-based, randomised controlled trial

BACKGROUND The continued presence of polio in northern India poses challenges to the interruption of wild poliovirus transmission and the management of poliovirus risks in the post-eradication era. We aimed to assess the current immunity profile after routine doses of trivalent oral poliovirus vaccine (OPV) and numerous supplemental doses of type-1 monovalent OPV (mOPV1), and compared the effect of five vaccine formulations and dosages on residual immunity gaps. METHODS We did a community-based, randomised controlled trial of healthy infants aged 6-9 months at ten sites in Moradabad, India. Serum neutralising antibody was measured before infants were randomly assigned to a study group and given standard-potency or higher-potency mOPV1, intradermal fractional-dose inactivated poliovirus vaccine (IPV, GlaxoSmithKline), or intramuscular full-dose IPV from two different manufacturers (GlaxoSmithKline or Panacea). Follow-up sera were taken at days 7 and 28. Our primary endpoint was an increase of more than four times in antibody titres. We did analyses by per-protocol in children with a blood sample available before, and 28 days after, receiving study vaccine (or who completed study procedures). This trial is registered with Current Controlled Trials, number ISRCTN90744784. FINDINGS Of 1002 children enrolled, 869 (87%) completed study procedures (ie, blood sample available at day 0 and day 28). At baseline, 862 (99%), 625 (72%), and 418 (48%) had detectable antibodies to poliovirus types 1, 2, and 3, respectively. In children who were type-1 seropositive, an increase of more than four times in antibody titre was detected 28 days after they were given standard-potency mOPV1 (5/13 [38%]), higher-potency mOPV1 (6/21 [29%]), intradermal IPV (9/16 [56%]), GlaxoSmithKline intramuscular IPV (19/22 [86%]), and Panacea intramuscular IPV (11/13 [85%]). In those who were type-2 seronegative, 42 (100%) of 42 seroconverted after GlaxoSmithKline intramuscular IPV, and 24 (59%) of 41 after intradermal IPV (p<0·0001). 87 (90%) of 97 infants who were type-3 seronegative seroconverted after intramuscular IPV, and 21 (36%) of 49 after intradermal IPV (p<0·0001). INTERPRETATION Supplemental mOPV1 resulted in almost total seroprevalence against poliovirus type 1, which is consistent with recent absence of poliomyelitis cases; whereas seroprevalence against types 2 and 3 was expected for routine vaccination histories. The immunogenicity of IPV produced in India (Panacea) was similar to that of an internationally manufactured IPV (GSK). Intradermal IPV was less immunogenic.