Global, Regional, and National Estimates of Rotavirus Mortality in Children <5 Years of Age, 2000-2013.

BACKGROUND: Rotavirus vaccine is recommended for routine use in all countries globally. To facilitate decision making on rotavirus vaccine adoption by countries, help donors prioritize investments in health interventions, and monitor vaccine impact, we estimated rotavirus mortality for children <5 years of age from 2000 to 2013. METHODS: We searched PubMed using the keyword "rotavirus" to identify studies that met each of the following criteria: data collection midpoint in year 1998 or later, study period of a 12-month increment, and detection of rotavirus infection by enzyme immunoassay in at least 100 children <5 years of age who were hospitalized with diarrhea and systematically enrolled through active surveillance. We also included data from countries that participated in the World Health Organization (WHO)-coordinated rotavirus surveillance network between 2008 and 2013 that met these criteria. To predict the proportion of diarrhea due to rotavirus, we constructed a multiple linear regression model. To determine the number of rotavirus deaths in children <5 years of age from 2000 to 2013, we multiplied annual, country-specific estimates of the proportion of diarrhea due to rotavirus from the regression model by the annual number of WHO-estimated child deaths caused by diarrhea in each country. RESULTS: Globally, we estimated that the number of rotavirus deaths in children <5 years of age declined from 528 000 (range, 465 000-591 000) in 2000 to 215 000 (range, 197 000-233 000) in 2013. The predicted annual rotavirus detection rate from these studies declined slightly over time from 42.5% (95% confidence interval [CI], 37.4%-47.5%) in 2000 to 37.3% (95% CI, 34.2%-40.5%) in 2013 globally. In 2013, an estimated 47 100 rotavirus deaths occurred in India, 22% of all rotavirus deaths that occurred globally. Four countries (India, Nigeria, Pakistan, and Democratic Republic of Congo) accounted for approximately half (49%) of all estimated rotavirus deaths in 2013. DISCUSSION: While rotavirus vaccine had been introduced in >60 countries worldwide by the end of 2013, the majority of countries using rotavirus vaccine during the review period were low-mortality countries and the impact of rotavirus vaccine on global estimates of rotavirus mortality has been limited. Continued monitoring of rotavirus mortality rates and deaths through rotavirus surveillance will aid in monitoring the impact of vaccination.

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.).

Intestinal immunity is a determinant of clearance of poliovirus after oral vaccination.

BACKGROUND: Response to challenge with live, attenuated, oral polio vaccine (OPV) is a measure of immunity induced by prior immunization. METHODS: Using stool samples from a study from Oman in which an initial schedule of inactivated polio vaccine (IPV) was followed by an OPV type 1 challenge, we quantitated virus shed, sequenced capsid proteins of recovered virus, and developed assays for neutralization of poliovirus and mucosal immunoglobulin A (IgA) detection. RESULTS: Neutralizing activity correlated with detection of polio-specific IgA in stool suspensions collected 7 days after OPV type 1 challenge. Both neutralization and IgA in stool were associated with cessation of virus shedding by day 7. Rapid development of an IgA response with cessation of shedding suggests that IPV primed for the early response to challenge. Correlation of neutralization activity and IgA detection provides evidence that polio-specific IgA intestinal antibody is a determinant of mucosal shedding/transmission and that IgA functions through neutralization of virus. In contrast, neither presence nor quantity of serum or intestinal antibody induced by IPV prior to challenge correlated with cessation of shedding. CONCLUSIONS: These assays provide an opportunity to study other immunization schedules to gain a broader understanding of the appearance and duration of a protective mucosal response to polio vaccination.

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).

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.)

Randomized trial of type 1 and type 3 oral monovalent poliovirus vaccines in newborns in Africa.

BACKGROUND: The Global Polio Eradication Initiative aims to eradicate wild poliovirus by the end of 2012. Therefore, more-immunogenic polio vaccines, including monovalent oral poliovirus vaccines (mOPVs), are needed for supplemental immunization activities. This trial assessed the immunogenicity of monovalent types 1 and 3, compared with that of trivalent oral poliovirus vaccine (tOPV), in South Africa. METHODS: We conducted a blinded, randomized, 4-arm controlled trial comparing the immunogenicity of a single dose of mOPV1 (from 2 manufacturers) and mOPV3 (from 1 manufacturer), given at birth, with the immunogenicity of tOPV. RESULTS: Eight hundred newborns were enrolled; 762 (95%) were included in the analysis. At 30 days after vaccine administration, seroconversion to poliovirus type 1 was 73.4% and 76.4% in the 2 mOPV1 arms, compared with 39.1% in the tOPV arm (P < .0000001), and seroconversion to poliovirus type 3 was 58.0% in the mOPV3 arm, compared with 21.2% in the tOPV arm (P < .0000001). The vaccines were well tolerated, and no adverse events were attributed to trial interventions. CONCLUSION: A dose of mOPV1 or mOPV3 at birth was superior to that of tOPV in inducing type-specific seroconversion in this sub-Saharan African population. Our results support continued use of mOPVs in supplemental immunization activities in countries where poliovirus types 1 or 3 circulate. Clinical Trials Registration. ISRCTN18107202.

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.

Monovalent type 1 oral poliovirus vaccine in newborns.

BACKGROUND: In 1988, the World Health Assembly resolved to eradicate poliomyelitis. Although substantial progress toward this goal has been made, eradication remains elusive. In 2004, the World Health Organization called for the development of a potentially more immunogenic monovalent type 1 oral poliovirus vaccine. METHODS: We conducted a trial in Egypt to compare the immunogenicity of a newly licensed monovalent type 1 oral poliovirus vaccine with that of a trivalent oral poliovirus vaccine. Subjects were randomly assigned to receive one dose of monovalent type 1 oral poliovirus vaccine or trivalent oral poliovirus vaccine at birth. Thirty days after birth, a single challenge dose of monovalent type 1 oral poliovirus vaccine was administered in all subjects. Shedding of serotype 1 poliovirus was assessed through day 60. RESULTS: A total of 530 subjects were enrolled, and 421 fulfilled the study requirements. Thirty days after the study vaccines were administered, the rate of seroconversion to type 1 poliovirus was 55.4% in the monovalent-vaccine group, as compared with 32.1% in the trivalent-vaccine group (P<0.001). Among those with a high reciprocal titer of maternally derived antibodies against type 1 poliovirus (>64), 46.0% of the subjects in the monovalent-vaccine group underwent seroconversion, as compared with 21.3% in the trivalent-vaccine group (P<0.001). Seven days after administration of the challenge dose of monovalent type 1 vaccine, a significantly lower proportion of subjects in the monovalent-vaccine group than in the trivalent-vaccine group excreted type 1 poliovirus (25.9% vs. 41.5%, P=0.001). None of the serious adverse events reported were attributed to the trial interventions. CONCLUSIONS: When given at birth, monovalent type 1 oral poliovirus vaccine is superior to trivalent oral poliovirus vaccine in inducing humoral antibodies against type 1 poliovirus, overcoming high preexisting levels of maternally derived antibodies, and increasing the resistance to excretion of type 1 poliovirus after administration of a challenge dose. (Current Controlled Trials number, ISRCTN76316509.)

Accounting for model uncertainty in estimating global burden of disease.

OBJECTIVE: To illustrate the effects of failing to account for model uncertainty when modelling is used to estimate the global burden of disease, with specific application to childhood deaths from rotavirus infection. METHODS: To estimate the global burden of rotavirus infection, different random-effects meta-analysis and meta-regression models were constructed by varying the stratification criteria and including different combinations of covariates. Bayesian model averaging was used to combine the results across models and to provide a measure of uncertainty that reflects the choice of model and the sampling variability. FINDINGS: In the models examined, the estimated number of child deaths from rotavirus infection varied between 492,000 and 664,000. While averaging over the different models' estimates resulted in a modest increase in the estimated number of deaths (541,000 as compared with the World Health Organization's estimate of 527,000), the width of the 95% confidence interval increased from 105,000 to 198,000 deaths when model uncertainty was taken into account. CONCLUSION: Sampling variability explains only a portion of the overall uncertainty in a modelled estimate. The uncertainty owing to both the sampling variability and the choice of model(s) should be given when disease burden results are presented. Failure to properly account for uncertainty in disease burden estimates may lead to inappropriate uses of the estimates and inaccurate prioritization of global health needs.

A mid-term assessment of progress towards the immunization coverage goal of the Global Immunization Vision and Strategy (GIVS).

BACKGROUND: The Global Immunization Vision and Strategy (GIVS) (2006-2015) aims to reach and sustain high levels of vaccine coverage, provide immunization services to age groups beyond infancy and to those currently not reached, and to ensure that immunization activities are linked with other health interventions and contribute to the overall development of the health sector. OBJECTIVE: To examine mid-term progress (through 2010) of the immunization coverage goal of the GIVS for 194 countries or territories with special attention to data from 68 countries which account for more than 95% of all maternal and child deaths. METHODS: We present national immunization coverage estimates for the third dose of diphtheria and tetanus toxoid with pertussis (DTP3) vaccine and the first dose of measles containing vaccine (MCV) during 2000, 2005 and 2010 and report the average annual relative percent change during 2000-2005 and 2005-2010. Data are taken from the WHO and UNICEF estimates of national immunization coverage, which refer to immunizations given during routine immunization services to children less than 12 months of age where immunization services are recorded. RESULTS: Globally DTP3 coverage increased from 74% during 2000 to 85% during 2010, and MCV coverage increased from 72% during 2000 to 85% during 2010. A total of 149 countries attained or were on track to achieve the 90% coverage goal for DTP3 (147 countries for MCV coverage). DTP3 coverage ≥ 90% was sustained between 2005 and 2010 by 99 countries (98 countries for MCV). Among 68 priority countries, 28 countries were identified as having made either insufficient or no progress towards reaching the GIVS goal of 90% coverage by 2015 for DTP3 or MCV. DTP3 and MCV coverage remained < 70% during 2010 for 16 and 21 priority countries, respectively. CONCLUSION: Progress towards GIVS goals highlights improvements in routine immunization coverage, yet it is troubling to observe priority countries with little or no progress during the past five years. These results highlight that further efforts are needed to achieve and maintain the global immunization coverage goals.