Evolving epidemiology of poliovirus serotype 2 following withdrawal of the serotype 2 oral poliovirus vaccine.

Although there have been no cases of serotype 2 wild poliovirus for more than 20 years, transmission of serotype 2 vaccine-derived poliovirus (VDPV2) and associated paralytic cases in several continents represent a threat to eradication. The withdrawal of the serotype 2 component of oral poliovirus vaccine (OPV2) was implemented in April 2016 to stop VDPV2 emergence and secure eradication of all serotype 2 poliovirus. Globally, children born after this date have limited immunity to prevent transmission. Using a statistical model, we estimated the emergence date and source of VDPV2s detected between May 2016 and November 2019. Outbreak response campaigns with monovalent OPV2 are the only available method to induce immunity to prevent transmission. Yet our analysis shows that using monovalent OPV2 is generating more paralytic VDPV2 outbreaks with the potential for establishing endemic transmission. A novel OPV2, for which two candidates are currently in clinical trials, is urgently required, together with a contingency strategy if this vaccine does not materialize or perform as anticipated.

Zinc supplementation fails to increase the immunogenicity of oral poliovirus vaccine: a randomized controlled trial.

BACKGROUND: Polio eradication remains a challenge in Pakistan and the causes for the failure to eradicate poliomyelitis are complex. Undernutrition and micronutrient deficiencies, especially zinc deficiency, are major public health problems in Pakistan and could potentially affect the response to enteric vaccines, including oral poliovirus vaccine (OPV). OBJECTIVE: To assess the impact of zinc supplementation among infants on immune response to oral poliovirus vaccine (OPV). METHODS: A double-blind, randomized placebo-controlled trial was conducted in newborns (aged 0-14 days). Subjects were assigned to either receive 10mg of zinc or placebo supplementation daily for 18 weeks. Both groups received OPV doses at birth, at 6 weeks, 10 weeks and 14 weeks. Data was collected on prior immunization status, diarrheal episodes, breastfeeding practices and anthropometric measurements at recruitment and at 6 and 18 weeks. Blood samples were similarly collected to determine the antibody response to OPV and for micronutrient analysis. Logistic regression was used to determine the relationship between seroconversion and zinc status. RESULTS: Overall, 404 subjects were recruited. At recruitment, seropositivity was already high for poliovirus (PV) serotype 1 (zinc: 91.1%; control: 90.5%) and PV2 (90.0%; 92.7%), with lower estimates for PV3 (70.0%; 64.8%). By week 18, the proportion of subjects with measured zinc levels in the normal range (i.e. ≥60 µg/dL) was significantly greater in the intervention group compared to the control group (71.9%; 27.4%; p<0.001). No significant difference in seroconversion was demonstrated between the groups for PV1, PV2, or PV3. CONCLUSIONS: There was no effect of zinc supplementation on OPV immunogenicity. These conclusions were confirmed when restricting the analysis to those with measured higher zinc levels.

A study evaluating poliovirus antibodies and risk factors associated with polio seropositivity in low socioeconomic areas of Pakistan.

BACKGROUND: Seroprevalence studies provide important data on performance of immunization programs, susceptible groups and populations at-risk of future outbreaks. Identifying risk factors that affect seroconversion of the oral polio vaccine (OPV) will enable the polio eradication initiatives to increase seroprevalence. This paper describes the first population-based seroprevalence survey in Pakistan. METHODS: This study evaluated the seroprevalence of poliovirus (PV) types 1, 2, and 3 antibodies to OPV in an illustrative sample of 554 subjects 6-11 months of age in three geographic locations of Pakistan (Lahore, Karachi, and Peshawar) representing a low socioeconomic at-risk populations. Antibody titers were measured and sero protection rates and geometric median titers were compared among different geographic regions and populations, as were demographics and OPV vaccination history collected by questionnaire. Univariate and multivariate analyses were conducted on subject characteristics to assess for potential risk factors for failure to sero-convert. RESULTS: The average seroprevalence of PV1, PV2, and PV3 was 96.0%, 87.9% and 86.7%, respectively. The lowest sero protection rate for all three serotypes was for Karachi with 90.2%, 73.8%, and 78.8% for PV1, PV2, and PV3, respectively. Significant regional variation in PV3 seroprevalence was found (range: 74.2-100%). In the univariate analysis, age, total and campaign OPV doses were associated with higher seroprevalence, whereas stunting, respondent education and diarrhea in the past six months were significant risk factors for failure to sero-convert. CONCLUSIONS: These findings demonstrate consistently high levels of antibody response to PV1 and more geographically varied response to PV2 and PV3. Additionally, important risk factors affecting seropositivity were identified.

Mass vaccination campaigns for polio eradication: an essential strategy for success.

Effective vaccines against poliomyelitis became available in the mid-1950s and early 1960s. Mass campaigns were an integral part of early control efforts. Thereafter, polio vaccines were used largely in routine childhood programs. The resolution in 1988 to eradicate polio globally led to the development of appropriate strategies to achieve this goal, including mass vaccination campaigns (i.e., national immunization days, sub-national immunization days and mop-up activities), to achieve the highest possible coverage in the shortest possible time. Unlike other vaccines, mass campaign use of oral poliovirus vaccine enhances the immunogenicity of this vaccine, primarily due to: (1) the decrease in the prevalence of other enteroviruses that potentially interfere with seroconversion; and (2) the secondary spread of vaccine virus from vaccinees to close contacts, resulting in seroconversion of some unvaccinated contacts. To reach the highest possible coverage, detailed planning, meticulous execution, careful supervision and standardized monitoring are critical. A number of innovative approaches to improve the quality and/or coverage have become the 'standard' of supplemental immunization activities. These mass campaigns have led to dramatic decreases in the incidence of polio. This chapter reviews the scientific, operational and programmatic data on mass campaign use of polio vaccines, and summarize the lessons learnt from implementing the mass vaccination strategies used to eradicate poliomyelitis globally.

Persistence of vaccine-derived poliovirus following a mass vaccination campaign in Cuba: implications for stopping polio vaccination after global eradication.

BACKGROUND: With substantial progress made toward polio eradication, developing the appropriate strategy for discontinuing global oral poliovirus vaccine (OPV) after global eradication becomes increasingly important. At issue is the theoretical risk of independent circulation of potentially virulent OPV-derived strains. Because Cuba uses OPV only in mass campaigns, it represents an ideal site to assess vaccine-derived poliovirus persistence. METHODS: Infants born after the 1997 biannual mass campaigns were evaluated for past (neutralizing antibody) or current (virus excretion) evidence of vaccine-derived poliovirus exposure. We obtained sera and/or stool specimens from 861 infants; a second serum from 218 infants. RESULTS: All stool specimens were poliovirus negative. Of 762 infants, 113 (14.8%) had initially detectable poliovirus type 1 antibody, 193 (25.3%) type 2, and 94 (12.3%) type 3. A precipitous antibody decline occurred in initially positive sera. CONCLUSIONS: Our results suggest that in a country with high population immunity, vaccine-derived virus is unlikely to establish ongoing circulation.

Sabin monovalent oral polio vaccines: review of past experiences and their potential use after polio eradication.

After global eradication of polio is achieved, there will be a need for stockpiles of vaccine to combat potential outbreaks of poliomyelitis caused by (1) unforeseen release of polioviruses, (2) continued circulation of vaccine-derived strains, or (3) prolonged replication of polioviruses in immunodeficient persons. We conducted a review of the literature to document the immunogenicity and safety of monovalent Sabin vaccines, considered ideal candidates for these situations. The National Library of Medicine archives were searched for the keywords "polio," "monovalent," and "vaccine." Seroconversion rates for monovalent Sabin type 1 ranged from 53% to 100% (median, 95%); for type 2, 77%-100% (median, 93%); and for type 3, 52%-100% (median, 85%). The risk of vaccine-associated poliomyelitis per million persons vaccinated ranged from.05 to 0.99 (type 1), 0-0.65 (type 2), and 1.18-8.91 (type 3). Single-dose monovalent Sabin vaccines are highly immunogenic and safe and should be considered for stockpiles of vaccine to provide an effective response to potential outbreaks of poliomyelitis in the post-eradication period.

Poliomyelitis eradication: progress, challenges for the end game, and preparation for the post-eradication era.

In 1988, the World Health Assembly resolved to eradicate poliomyelitis globally by the year 2000. Dramatic progress toward this goal has occurred: three of the six WHO regions (Region of the Americas, European Region, and Western Pacific Region) are now polio free; and the number of polio-endemic countries decreased from over 125 in 1988 to 30 in 1999. Intensified efforts currently are underway to reach the target as soon as possible after 2000 in the three remaining polio-endemic WHO regions (African Region, Eastern Mediterranean Region, and South-East Asia Region). Even in polio-endemic regions, many countries are already polio free as the geographic extent of poliovirus shrinks while others. especially those experiencing conflict and war, pose substantial challenges to implementing the proven polio eradication strategies. Increasing attention and research now are devoted to the certification of polio eradication in the polio-free regions (that will include the first phase of implementing the Global Plan of Action for the laboratory containment of wild poliovirus) and formulating a policy for stopping all polio vaccination once eradication, containment, and global certification have been achieved. This report outlines the progress toward polio eradication and highlights some of the remaining issues and challenges that must be addressed before polio becomes a disease that future generations know only by history.

Possible global strategies for stopping polio vaccination and how they could be harmonized.

One of the challenges of the polio eradication initiative over the next few years will be the formulation of an optimal strategy for stopping poliovirus vaccination after global certification of polio eradication has been accomplished. This strategy must maximize the benefits and minimize the risks. A number of strategies are currently under consideration, including: (i) synchronized global discontinuation of use of oral poliovirus vaccine (OPV); (ii) regional or subregional coordinated OPV discontinuation; and (iii) moving from trivalent to bivalent or monovalent OPV. Other options include moving from OPV to global use of IPV for an interim period before cessation of IPV use (to eliminate circulation of vaccine-derived poliovirus, if necessary) or development of new OPV strains that are not transmissible. Each of these strategies is associated with specific advantages (financial benefits for OPV discontinuation) and disadvantages (cost of switch to IPV) and inherent uncertainties (risk of continued poliovirus circulation in certain populations or prolonged virus replication in immunodeficient persons). An ambitious research agenda addresses the remaining questions and issues. Nevertheless, several generalities are already clear. Unprecedented collaboration between countries, regions, and indeed the entire world will be required to implement a global OPV discontinuation strategy Regulatory approval will be needed for an interim bivalent OPV or for monovalent OPV in many countries. Manufacturers will need sufficient lead time to produce sufficient quantities of IPV Finally, the financial implications for any of these strategies need to be considered. Whatever strategy is followed it will be necessary to stockpile supplies of a poliovirus-containing vaccine (most probably all three types of monovalent OPV), and to develop contingency plans to respond should an outbreak of polio occur after stopping vaccination.

Measles eradication: is it in our future?

Measles eradication would avert the current annual 1 million deaths and save the $1.5 billion in treatment and prevention costs due to measles in perpetuity. The authors evaluate the biological feasibility of eradicating measles according to 4 criteria: (1) the role of humans in maintaining transmission, (2) the availability of accurate diagnostic tests, (3) the existence of effective vaccines, and (4) the need to demonstrate elimination of measles from a large geographic area. Recent successes in interrupting measles transmission in the United States, most other countries in the Western Hemisphere, and selected countries in other regions provide evidence for the feasibility of global eradication. Potential impediments to eradication include (1) lack of political will in some industrialized countries, (2) transmission among adults, (3) increasing urbanization and population density, (4) the HIV epidemic, (5) waning immunity and the possibility of transmission from subclinical cases, and (6) risk of unsafe injections. Despite these challenges, a compelling case can be made in favor of measles eradication, and the authors believe that it is in our future. The question is when.

Trial of a supplemental dose of four poliovirus vaccines.

BACKGROUND: The immunogenicity of oral poliovirus vaccine (OPV), particularly the type 3 component, is lower in infants in most developing countries than in infants in industrialized countries. We conducted a multicenter trial in Oman to evaluate the response to a supplemental dose of four poliovirus vaccine formulations. METHODS: At nine months of age, infants were randomly assigned to receive inactivated-poliovirus vaccine (IPV), administered subcutaneously; trivalent OPV manufactured in the United States or in Europe; or monovalent type 3 OPV. Serum samples were collected at enrollment and 7 and 30 days later. All of the infants had previously received five doses of OPV. RESULTS: We enrolled 1025 infants; 785 (76.6 percent) met all the study requirements. At enrollment, 96.8 percent of the infants were seropositive for poliovirus type 1, 98.0 percent for type 2, and 88.0 percent for type 3. At 30 days there were no significant increases in type 3 seroprevalence or in the median antibody titer in the groups of infants who received OPV. Among the recipients of IPV, type 3 seroprevalence increased from 87.8 percent at enrollment to 97.1 percent at 30 days (P<0.001), and the median antibody titer increased from 1:228 to 1:1448 or higher (P<0.001). The rapid initial increase in the antibody titer suggests a secondary immune response. CONCLUSIONS: A supplemental dose of IPV has excellent immunogenicity and leads to increases in the titer of antibodies against type 3 poliovirus, whereas supplemental doses of the oral vaccines do not have these effects.

Widespread paralytic poliomyelitis in Pakistan: A case-control study to determine risk factors and implications for poliomyelitis eradication.

Despite substantial efforts to eradicate poliomyelitis by administering oral poliovirus vaccine through routine immunization and annual national immunization days (NIDs), Pakistan reported 22% (1147) of the worldwide cases in 1997. Reasons for continued high poliomyelitis incidence include failure to vaccinate, vaccine failure, or inadequate immunization strategies. A case-control study was conducted to measure vaccination status and reasons for undervaccination among 66 poliomyelitis cases and 130 age- and neighborhood-matched controls. Cases were undervaccinated through routine immunization (matched odds ratio [MOR], 0.3; 95% confidence interval [CI], 0.1-0.5); however, NID immunization was similar for cases and controls (MOR, 0.6; 95% CI, 0.3-1.2). Reasons for undervaccination included not being informed, considering vaccination unimportant, and long distances to vaccination sites. Failure to vaccinate through routine immunization was a major risk factor for poliomyelitis in Pakistan. Successful NIDs alone will not interrupt poliovirus circulation in Pakistan, and children remain at risk unless routine immunization is strengthened or additional supplementary immunization is provided.

Factors determining prevalence of maternal antibody to measles virus throughout infancy: a review.

The effectiveness of vaccination against measles, the leading cause of vaccine-preventable deaths in infants globally, is greatly impacted by the level of maternal antibody to measles virus (or "measles maternal antibody"; MMA) during infancy. Variation in the prevalence of maternal antibody to measles virus between infant populations across countries and sociodemographic strata is poorly understood. We reviewed the literature on the prevalence of MMA, focusing on 3 principal determinants: starting level of maternal antibody, placental transfer of maternal antibody, and rate of decay of maternal antibody after birth. Our review identified placental transfer as an important determinant, with greater efficiency found in studies performed in developed countries. Placental transfer was influenced by gestational age, human immunodeficiency virus infection, and malaria. Antibody levels in mothers varied widely between countries, although predictably according to vaccination status within populations. Rates of antibody decay across studies were similar. Future studies should evaluate the utility of the cord blood level of MMA as a predictor of vaccine efficacy in infancy; inclusion of World Health Organization international reference sera will facilitate comparisons. Greater understanding of the determinants of the prevalence of MMA will help national policy makers determine the appropriate age for measles vaccination.

Disease eradication as a public health strategy: a case study of poliomyelitis eradication.

Disease eradication as a public health strategy was discussed at international meetings in 1997 and 1998. In this article, the ongoing poliomyelitis eradication initiative is examined using the criteria for evaluating candidate diseases for eradication proposed at these meetings, which covered costs and benefits, biological determinants of eradicability (technical feasibility) and societal and political considerations (operational feasibility). The benefits of poliomyelitis eradication are shown to include a substantial investment in health services delivery, the elimination of a major cause of disability, and far-reaching intangible effects, such as establishment of a "culture of prevention". The costs are found to be financial and finite, despite some disturbances to the delivery of other health services. The "technical" feasibility of poliomyelitis eradication is seen in the absence of a non-human reservoir and the presence of both an effective intervention and delivery strategy (oral poliovirus vaccine and national immunization days) and a sensitive and specific diagnostic tool (viral culture of specimens from acute flaccid paralysis cases). The certification of poliomyelitis eradication in the Americas in 1994 and interruption of endemic transmission in the Western Pacific since March 1997 confirm the operational feasibility of this goal. When the humanitarian, economic and consequent benefits of this initiative are measured against the costs, a strong argument is made for eradication as a valuable disease control strategy.

Stopping poliovirus vaccination after eradication: issues and challenges.

Since 1988 reported polio cases worldwide have declined by about 85% and the number of known or suspected polioendemic countries has decreased from over 120 to less than 50. With eradication of poliomyelitis approaching, issues potentially affecting when and how vaccination against poliovirus can be stopped become extremely important. Because of the potential risks and benefits inherent in such a decision, the best available science, a risk-benefit analysis, contingency plans, a stock pile of poliovirus vaccines, and the endorsement by the global policy-making committees will all be needed before vaccination can be discontinued. The scientific basis for stopping polio immunization has been reviewed by WHO. This Round Table article summarizes the current state of knowledge, provides an update on the processes and timelines for certification, containment, and stopping vaccination, and highlights some of the unanswered scientific questions that will be addressed by further research. These include whether transmission of vaccine-derived poliovirus strains could be sustained so that poliomyelitis could re-emerge in a future unvaccinated population and whether prolonged excretion of vaccine-derived poliovirus from individuals with immune deficiencies could be a mechanism through which this could occur.

Poliovirus vaccines. Progress toward global poliomyelitis eradication and changing routine immunization recommendations in the United States.

Poliomyelitis prevention in the United States has relied virtually exclusively on OPV during the past 30 years. Starting in 1997, a major change in the poliomyelitis vaccination policy occurred, facilitated by substantial progress toward worldwide poliomyelitis eradication. A sequential schedule of IPV followed by OPV became the preferred means to prevent poliomyelitis, although an all-OPV and an all-IPV schedule were considered acceptable alternatives. In 1999, two doses of IPV were recommended to start the primary series, followed by two doses of either poliovirus vaccine. As of January 2000, an all-IPV schedule is currently being implemented in the United States for routine childhood vaccination. Several unusual features are associated with the major public health policy change from an all-OPV to a sequential schedule, including (1) the process of involving a neutral party (i.e., the IOM); (2) the perceived concerns expressed before the change in policy with regard to provider and parent compliance, which could affect the hard-earned gains in raising immunization coverage rates; (3) the ethical issues surrounding the change (e.g., societal versus individual protection) and the influence that a single case of VAPP may have on national policy; (4) the relative lack of importance of cost-effectiveness data; and (5) the weight of progress in the global polio eradication initiative spurring the change in the United States and, increasingly, in other industrialized countries. The IOM assisted in the evaluation of the national poliomyelitis vaccination policy in 1977 and again in 1988. The 1988 review recommended that a sequential IPV-OPV schedule be considered at such time that a combination vaccine becomes available. Also, the IOM raised several important questions. Extensive research to address the questions raised by the IOM had been conducted so that, in 1996, more data were available for the decision-making process. The primary reasons for the change in vaccination policy were (1) the continued occurrence of VAPP in the absence of indigenously acquired wildtype poliovirus-associated paralytic disease, (2) the reduced risk for importation and spread of wild-type poliovirus caused by the progress of the global polio eradication initiative, (3) evidence from vaccine trials that combined IPV-OPV schedules are safe and immunogenic, and (4) maintenance of high levels of population immunity to poliovirus. The global effect of a national change in poliomyelitis vaccination policy was also considered in this policy-making process. Some members of the public health and medical communities raised objections that an increased reliance on IPV in the United States could lead other countries, especially developing countries, to inappropriately abandon OPV and increase reliance on IPV for routine vaccination. Experience from the global smallpox eradication campaign indicated that this scenario was unlikely. The United States ceased vaccinating against smallpox in 1971, 6 years before smallpox was eliminated from the world, without jeopardizing the global smallpox campaign. Subsequently, the effect on the global eradication initiative has been negligible. This article illustrates the potential discrepancy between expressed theoretic concerns about the number of injections and the actual practice once vaccination policy recommendations become the standard of care and that appropriate training and education can overcome these initial concerns. The authors found that compliance with the recommended use of IPV for the first and second doses as part of the sequential schedule was high, independent of socioeconomic status and ethnicity. The need for additional injections did not present a barrier to completion of the recommended childhood immunization schedule. (ABSTRACT TRUNCATED)

Risk factors for diphtheria: a prospective case-control study in the Republic of Georgia, 1995-1996.

The large-scale resurgence of diphtheria in the former Soviet Union offered a unique opportunity to evaluate risk factors for the transmission of respiratory diphtheria; therefore, a prospective case-control study was done in the republic of Georgia. In total, 218 diphtheria cases (hospitalized between October 1995 and March 1996) and 408 matched controls participated. One hundred cases (45%) were /=15 years of age (range: <1 to 75 years). In the multivariate analyses, the following risk factors were found to be significant: lack of vaccination (matched odds ratio [mOR]=19.2), household exposure to diphtheria (mOR=7.4), exposure to skin lesions (mOR=5.8), history of eczema (mOR=3.4), fever with myalgia prior to illness (mOR=2.6), having tonsils (mOR=4.4), sharing a bed (mOR=1.9), sharing cups and glasses (mOR=2.7), and taking a bath less than once a week (mOR=2.6). These findings emphasize primary prevention through immunizations, secondary prevention following exposure to diphtheria (and to suspicious skin lesions), and adherence to strict standards of personal hygiene.

Epidemic diphtheria in the Republic of Georgia, 1993-1996: risk factors for fatal outcome among hospitalized patients.

Epidemic diphtheria reemerged in the republic of Georgia in November 1993. To identify risk factors for fatal outcomes, clinical and epidemiologic data on all hospitalized diphtheria patients were examined. Medical charts of patients from 1993-1995 were reviewed. A total of 659 cases and 68 deaths were identified (case fatality rate [CFR] = 10.3%). Fifty-two percent of all cases and 68% of deaths were in children 3 days) between onset of symptoms to antitoxin treatment were significantly associated with fatal outcomes. Immunization of children and 40- to 49-year-old adults was required to rapidly control the epidemic.

Immunogenicity of tetanus-diphtheria toxoids (Td) among Ukrainian adults: implications for diphtheria control in the Newly Independent States of the Former Soviet Union.

After 30 years of control, epidemic diphtheria returned to the Soviet Union in 1990. To develop control strategies, the immunogenicity of the tetanus and diphtheria toxoids (Td) vaccine was assessed. Workers who were 18-67 years old received two Td immunizations separated by 30 days. A neutralization assay determined diphtheria antitoxin (DAT) on enrollment and on days 7, 30, 60, and 425. On enrollment, 43.0% of 488 workers had DAT <0.1 IU/mL. After one dose, 88.5% had DAT >/=0.1 IU/mL, after two doses, 92.2% had >/=0.1 IU/mL and >90% of participants <30 or >/=50 years of age attained >/=1.0 IU/mL; however, only 78.4% of those who were 30-39 years old and 51.8% of those who were 40-49 years old achieved >/=1.0 IU/mL after two doses. To control the epidemic in Ukraine, one Td dose should be administered to virtually the entire population (persons 30-49 years old require three doses of Td for optimal individual protection and to maximize population immunity).

Evaluation of a single dose of diphtheria toxoid among adults in the Republic of Georgia, 1995: immunogenicity and adverse reactions.

To determine the immunogenicity and safety of a single dose of diphtheria toxoid among adults, blood samples for detecting serum antitoxin levels were obtained from 18- to 59-year-old subjects (n=248) before and 30 days after immunization with Td (tetanus-diphtheria toxoids; manufactured by Serum Institute of India). By day 30, the seroprevalence of antitoxin levels >/=0.1 IU/mL increased from 22.6% to 81.5%; median antitoxin levels increased from 0.01 to 4.0 IU/mL. These parameters were lowest among subjects who were 40-59 years old, especially among those 40-49 years old. Adverse reactions (local redness, swelling, induration, fever>39 degrees C) were reported by 5.3% of participants. Our findings suggest that, in general, one dose of the Indian-produced Td vaccine is efficacious and safe in inducing an adequate immune response against diphtheria in adults; however, in Georgia, persons 40-59 years old, especially those 40-49 years old, will require additional doses of toxoid to achieve protective levels of antitoxin.