Facility-Associated Release of Polioviruses into Communities-Risks for the Posteradication Era.

The Global Polio Eradication Initiative continues to make progress toward the eradication target. Indigenous wild poliovirus (WPV) type 2 was last detected in 1999, WPV type 3 was last detected in 2012, and over the past 2 years WPV type 1 has been detected only in parts of 2 countries (Afghanistan and Pakistan). Once the eradication of poliomyelitis is achieved, infectious and potentially infectious poliovirus materials retained in laboratories, vaccine production sites, and other storage facilities will continue to pose a risk for poliovirus reintroduction into communities. The recent breach in containment of WPV type 2 in an inactivated poliovirus vaccine manufacturing site in the Netherlands prompted this review, which summarizes information on facility-associated release of polioviruses into communities reported over >8 decades. Successful polio eradication requires the management of poliovirus containment posteradication to prevent the consequences of the reestablishment of poliovirus transmission.

Progress Toward Poliovirus Containment Implementation - Worldwide, 2018-2019.

Among the three wild poliovirus (WPV) types, type 2 (WPV2) was declared eradicated globally by the Global Commission for the Certification of Poliomyelitis Eradication (GCC) in 2015. Subsequently, in 2016, a global withdrawal of Sabin type 2 oral poliovirus vaccine (OPV2) from routine use, through a synchronized switch from the trivalent formulation of oral poliovirus vaccine (tOPV, containing vaccine virus types 1, 2, and 3) to the bivalent form (bOPV, containing types 1 and 3), was implemented. WPV type 3 (WPV3), last detected in 2012 (1), will possibly be declared eradicated in late 2019.* To ensure that polioviruses are not reintroduced to the human population after eradication, World Health Organization (WHO) Member States committed in 2015 to containing all polioviruses in poliovirus-essential facilities (PEFs) that are certified to meet stringent containment criteria; implementation of containment activities began that year for facilities retaining type 2 polioviruses (PV2), including type 2 oral poliovirus vaccine (OPV) materials (2). As of August 1, 2019, 26 countries have nominated 74 PEFs to retain PV2 materials. Twenty-five of these countries have established national authorities for containment (NACs), which are institutions nominated by ministries of health or equivalent bodies to be responsible for poliovirus containment certification. All designated PEFs are required to be enrolled in the certification process by December 31, 2019 (3). When GCC certifies WPV3 eradication, WPV3 and vaccine-derived poliovirus (VDPV) type 3 materials will also be required to be contained, leading to a temporary increase in the number of designated PEFs. When safer alternatives to wild and OPV/Sabin strains that do not require containment conditions are available for diagnostic and serologic testing, the number of PEFs will decrease. Facilities continuing to work with polioviruses after global eradication must minimize the risk for reintroduction into communities by adopting effective biorisk management practices.

Progress Toward Poliovirus Containment Implementation - Worldwide, 2017-2018.

Substantial progress has been made since the World Health Assembly (WHA) resolved to eradicate poliomyelitis in 1988 (1). Among the three wild poliovirus (WPV) types, type 2 (WPV2) was declared eradicated in 2015, and type 3 (WPV3) has not been reported since 2012 (1). In 2017 and 2018, only Afghanistan and Pakistan have reported WPV type 1 (WPV1) transmission (1). When global eradication of poliomyelitis is achieved, facilities retaining poliovirus materials need to minimize the risk for reintroduction of poliovirus into communities and reestablishment of transmission. Poliovirus containment includes biorisk management requirements for laboratories, vaccine production sites, and other facilities that retain polioviruses after eradication; the initial milestones are for containment of type 2 polioviruses (PV2s). At the 71st WHA in 2018, World Health Organization (WHO) Member States adopted a resolution urging acceleration of poliovirus containment activities globally, including establishment by the end of 2018 of national authorities for containment (NACs) to oversee poliovirus containment (2). This report summarizes containment progress since the previous report (3) and outlines remaining challenges. As of August 2018, 29 countries had designated 81 facilities to retain PV2 materials; 22 of these countries had established NACs. Although there has been substantial progress, intensification of containment measures is needed.

Effect of buffer on the immune response to trivalent oral poliovirus vaccine in Bangladesh: a community based randomized controlled trial.

BACKGROUND: Polio eradication efforts have been hampered by low responses to trivalent oral poliovirus vaccine (tOPV) in some developing countries. Since stomach acidity may neutralize vaccine viruses, we assessed whether administration of a buffer solution could improve the immunogenicity of tOPV. METHODS: Healthy infants 4-6 weeks old in Sylhet, Bangladesh, were randomized to receive tOPV with or without a sodium bicarbonate and sodium citrate buffer at age 6, 10, and 14 weeks. Levels of serum neutralizing antibodies for poliovirus types 1, 2, and 3 were measured before and after vaccination, at 6 and 18 weeks of age, respectively. FINDINGS: Serologic response rates following 3 doses of tOPV for buffer recipients and control infants were 95% and 88% (P=.065), respectively, for type 1 poliovirus; 95% and 97% (P=.543), respectively, for type 2 poliovirus; and 90% and 89% (P=.79), respectively, for type 3 poliovirus. CONCLUSIONS: Administration of a buffer solution prior to vaccination was not associated with statistically significant increases in the immune response to tOPV; however, a marginal 7% increase (P=.065) in serologic response to poliovirus type 1 was observed. CLINICAL TRIALS REGISTRATION: NCT01579825.

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.

Expert review on poliovirus immunity and transmission.

Successfully managing risks to achieve wild polioviruses (WPVs) eradication and address the complexities of oral poliovirus vaccine (OPV) cessation to stop all cases of paralytic poliomyelitis depends strongly on our collective understanding of poliovirus immunity and transmission. With increased shifting from OPV to inactivated poliovirus vaccine (IPV), numerous risk management choices motivate the need to understand the tradeoffs and uncertainties and to develop models to help inform decisions. The U.S. Centers for Disease Control and Prevention hosted a meeting of international experts in April 2010 to review the available literature relevant to poliovirus immunity and transmission. This expert review evaluates 66 OPV challenge studies and other evidence to support the development of quantitative models of poliovirus transmission and potential outbreaks. This review focuses on characterization of immunity as a function of exposure history in terms of susceptibility to excretion, duration of excretion, and concentration of excreted virus. We also discuss the evidence of waning of host immunity to poliovirus transmission, the relationship between the concentration of poliovirus excreted and infectiousness, the importance of different transmission routes, and the differences in transmissibility between OPV and WPV. We discuss the limitations of the available evidence for use in polio risk models, and conclude that despite the relatively large number of studies on immunity, very limited data exist to directly support quantification of model inputs related to transmission. Given the limitations in the evidence, we identify the need for expert input to derive quantitative model inputs from the existing data.

Persistence of immunity following a single dose of inactivated poliovirus vaccine: a phase 4, open label, non-randomised clinical trial.

BACKGROUND: The polio eradication endgame required the withdrawal of Sabin type 2 from the oral poliovirus vaccine and introduction of one or more dose of inactivated poliovirus vaccine (IPV) into routine immunisation schedules. However, the duration of single-dose IPV immunity is unknown. We aimed to address this deficiency. METHODS: In this phase 4, open-label, non-randomised clinical trial, we assessed single-dose IPV immunity. Two groups of infants or children were screened: the first group had previously received IPV at 14 weeks of age or older (previous IPV group; age >2 years); the second had not previously received IPV (no previous IPV group; age 7-12 months). At enrolment, all participants received an IPV dose. Children in the no previous IPV group received a second IPV dose at day 30. Blood was collected three times in each group: on days 0, 7, and 30 in the previous IPV group and on days 0, 30, and 37 in the no previous IPV group. Poliovirus antibody was measured by microneutralisation assay. Immunity was defined as the presence of a detectable antibody or a rapid anamnestic response (ie, priming). We used the χ2 to compare proportions and the Mann-Whitney U test to assess continuous variables. To assess safety, vaccinees were observed for 30 min, caregivers for each participating child reported adverse events after each follow-up visit and were questioned during each follow-up visit regarding any adverse events during the intervening period. Adverse events were recorded and graded according to the severity of clinical symptoms. The study is registered with ClinicalTrials.gov, NCT03723837. FINDINGS: From Nov 18, 2018, to July 31, 2019, 502 participants enrolled in the study, 458 (255 [65%] boys and 203 [44%] girls) were included in the per protocol analysis: 234 (93%) in the previous IPV group and 224 (90%) in the no previous IPV group. In the previous IPV group, 28 months after one IPV dose 233 (>99%) of 234 children had persistence of poliovirus type 2 immunity (100 [43%] of 234 children were seropositive; 133 [99%] of 134 were seronegative and primed). In the no previous IPV group, 30 days after one IPV dose all 224 (100%) children who were type 2 poliovirus naive had seroconverted (223 [>99%] children) or were primed (one [<1%]). No adverse events were deemed attributable to study interventions. INTERPRETATION: A single IPV dose administered at 14 weeks of age or older is highly immunogenic and induces nearly universal type 2 immunity (seroconversion and priming), with immunity persisting for at least 28 months. The polio eradication initiative should prioritise first IPV dose administration to mitigate the paralytic burden caused by poliovirus type 2. FUNDING: WHO and Rotary International.

Cuba's Scientific Contributions to Global Polio Eradication.

Cuba eliminated polio in 1962 and was among the first countries to do so. Since then, only 20 cases of vaccine-derived paralytic poliomyelitis have been reported. Because Cuba used oral poliovirus vaccine exclusively in two mass campaigns usually in February and April each year, Sabin viruses were detected only within approximately 6-8 weeks after each annual campaign. This made Cuba a very attractive site to study the epidemiology of poliomyelitis in a tropical country without risk of secondary transmission of Sabin viruses for a large part of each year, an advantage over countries that used oral poliovirus vaccine continuously throughout the year in routine immunization programs. This report summarizes the unique scientific collaboration between Cuba's Ministry of Public Health and WHO, with participation by US scientists, in the global effort to eradicate polio. KEYWORDS Poliomyelitis, disease eradication, disease elimination, oral poliovirus vaccine, Sabin vaccine, inactivated poliovirus vaccine, Salk vaccine, Cuba, WHO.

Global Polio Eradication - Way Ahead.

In 1988, the World Health Assembly resolved to eradicate poliomyelitis by the year 2000. Although substantial progress was achieved by 2000, global polio eradication proved elusive. In India, the goal was accomplished in 2011, and the entire South-East Asia Region was certified as polio-free in 2014. The year 2016 marks the lowest wild poliovirus type 1 case count ever, the lowest number of polio-endemic countries (Afghanistan, Nigeria and Pakistan), the maintenance of wild poliovirus type 2 eradication, and the continued absence of wild poliovirus type 3 detection since 2012. The year also marks the Global Polio Eradication Initiative (GPEI) moving into the post-cessation of Sabin type 2, after the effort of globally synchronized withdrawal of Sabin type 2 poliovirus in April 2016. Sustained efforts will be needed to ensure polio eradication is accomplished, to overcome the access and security issues, and continue to improve the quality and reach of field operations. After that, surveillance (the "eyes and ears") will move further to the center stage. Sensitive surveillance will monitor the withdrawal of all Sabin polioviruses, and with facility containment, constitute the cornerstones for eventual global certification of wild poliovirus eradication. An emergency response capacity is essential to institute timely control measures should polio still re-emerge. Simultaneously, the public health community needs to determine whether and how to apply the polio-funded infrastructure to other priorities (after the GPEI funding has stopped). Eradication is the primary goal, but securing eradication will require continued efforts, dedicated resources, and a firm commitment by the global public health community.

Feasibility of conducting intradermal vaccination campaign with inactivated poliovirus vaccine using Tropis intradermal needle free injection system, Karachi, Pakistan.

BACKGROUND: Administration of intradermal fractional dose of inactivated poliovirus vaccine (fIPV) has proven to be safe and immunogenic; however, its intradermal application using needle and syringe is technically difficult and requires trained personnel. METHODS: We assessed feasibility of conducting an intradermal fIPV campaign in polio high risk neighborhood of Karachi using Tropis needle-free injector. During the one-day fIPV campaign, we measured average "application time" to administer fIPV with Tropis, collected ergonomic information and measured vaccine wastage. RESULTS: Eleven vaccinator teams, after two-day training, immunized 582 children between 4 months and 5 years of age. Average "application time" ranged from 35-75 seconds; the "application time" decreased with the number of children vaccinated from 68 to 38 seconds between 1st and 30th child. 10/11 (91%) vaccinator teams found no ergonomic issues; 1/11 (9%) assessed that it was not easy to remove air bubbles when filling the device. There was 0% vaccine loss reported. No adverse events following immunizations were reported. INTERPRETATION: We demonstrated that it is feasible, safe and efficient to use Tropis for the administration of fIPV in a campaign setting.

Monovalent type-1 oral poliovirus vaccine given at short intervals in Pakistan: a randomised controlled, four-arm, open-label, non-inferiority trial.

BACKGROUND: Supplementary immunisation activities with oral poliovirus vaccines (OPVs) are usually separated by 4 week intervals; however, shorter intervals have been used in security-compromised areas and for rapid outbreak responses. We assessed the immunogenicity of monovalent type-1 oral poliovirus vaccine (mOPV1) given at shorter than usual intervals in Karachi, Pakistan. METHODS: This was a multicentre, randomised, controlled, four-arm, open-label, non-inferiority trial done at five primary health-care centres in low-income communities in and around Karachi, Pakistan. Eligible participants were healthy newborn babies with a birthweight of at least 2·5 kg, for whom informed consent was provided by their parent or guardian, and lived less than 30 km from the study clinic. After receiving a birth dose of trivalent OPV, we enrolled and randomly assigned newborn babies (1:1:1:1) to receive two doses of mOPV1 with an interval of 1 week (mOPV1-1 week), 2 weeks (mOPV1-2 weeks), or 4 weeks (mOPV1-4 weeks) between doses, or two doses of bivalent OPV (bOPV) with an interval of 4 weeks between doses (bOPV-4 weeks). We gave the first study dose of OPV at age 6 weeks. We did the randomisation with a centrally generated, computerised allocation sequence with blocks of 16; participants' families and study physicians could not feasibly be masked to the allocations. Trial participants were excluded from local supplementary immunisation activities during the study period. The primary outcome was non-inferiority (within a 20% margin) between groups in seroconversion to type-1 poliovirus. The primary and safety analyses were done in the per-protocol population of infants who received all three doses of vaccine. This trial is registered with ClinicalTrials.gov, number NCT01586572, and is closed to new participants. FINDINGS: Between March 1, 2012, and May 31, 2013, we enrolled 1009 newborn babies, and randomly assigned 829 (82%) to treatment. 554 (67%) of the 829 babies were included in the per-protocol analysis. Proportions of seroconversion to type-1 poliovirus were 107/135 (79%, 95% CI 72·4-86·1) with mOPV1-1 week, 108/135 (80%, 73·2-86·8) with mOPV1-2 weeks, 129/148 (87%, 80·9-92·0) with mOPV1-4 weeks, and 107/136 (79%, 71·8-85·6) with bOPV-4 weeks. Non-inferiority was shown between groups and no significant differences were noted. Ten participants died during the trial. Seven of these deaths occurred during the lead-in period before randomisation (two from diarrhoea, five from unknown causes). Three infants died from sepsis after random assignment. No deaths were attributed to the procedures or vaccines. Additionally, we noted no events of vaccine-associated paralysis. INTERPRETATION: We identified no significant differences in responses to mOPV1 given with shorter intervals between doses than with the standard 4 week intervals. The short-interval strategy could be particularly beneficial when temporary windows of opportunity for safe access can be granted in areas of conflict--eg, during cease-fire periods. In such situations, we recommend shortening the interval between OPV doses to 7 days. FUNDING: World Health Organization.

Mucosal immunity and poliovirus vaccines: impact on wild poliovirus infection and transmission.

Since the resolution of the World Assembly in 1988 to eradicate polio globally, substantial progress toward this target has been achieved, but the final goal remains elusive. India and other tropical developing countries present a unique challenge because of the much lower oral poliovirus vaccine (OPV) immunogenicity compared to industrialized countries, both in terms of humoral and mucosal immunity. To overcome this challenge, further research is needed to elucidate the causes for the suboptimal OPV immunogenicity, better defining the optimal vaccine schedules and delivery strategies, developing and evaluating adjuvants to boost OPV immunogenicity, and improving the methods for directly measuring mucosal immunity.

Mucosal immunity to poliovirus.

The Global Polio Eradication Initiative (GPEI) currently based on use of oral poliovirus vaccine (OPV) has identified suboptimal immunogenicity of this vaccine as a major impediment to eradication, with a failure to induce protection against paralytic poliomyelitis in certain population segments in some parts of the world. The Mucosal Immunity and Poliovirus Vaccines: Impact on Wild Poliovirus Infection, Transmission and Vaccine Failure conference was organized to obtain a better understanding of the current status of global control of poliomyelitis and identify approaches to improve the immune responsiveness and effectiveness of the orally administered poliovirus vaccines in order to accelerate the global eradication of paralytic poliomyelitis.

Monovalent type 1 oral poliovirus vaccine among infants in India: report of two randomized double-blind controlled clinical trials.

BACKGROUND: To provide the polio eradication initiative with more immunogenic oral poliovirus vaccines (OPVs), we evaluated newly developed monovalent type 1 OPV (mOPV1) among infants in India. METHODS: Two double-blind randomized controlled clinical trials compared two mOPV1s (mOPV1 A and mOPV1 B) versus trivalent OPV (tOPV X) given at birth (trial I), or assessed two products of higher-potency mOPV1 (mOPV1 C and mOPV1 D) versus regular-potency mOPV1 (mOPV1 B) or tOPV Y given at birth and at 30 days (trial II). RESULTS: In trial I, 597 newborns were enrolled, 66 withdrawn or excluded, leaving 531 (88.9%) subjects for analysis. Seroconversion to poliovirus type 1 was 10.4% for mOPV1 A, 15.6% for mOPV1 B and 10.2% for tOPV X. In trial II, 718 newborns were enrolled, 135 withdrawn or excluded, leaving 583 (81.2%) subjects for analysis. Seroconversion to poliovirus type 1 following a birth dose was 15.1%, 19.7%, 18.0% and 10.6%, following the 30-day dose 87.1%, 89.2%, 84.4%, or 55.9%, and cumulative for both doses 90.4%, 90.3%, 89.5% and 61.9% for mOPV1s B, C, and D and tOPV Y, respectively. CONCLUSIONS: In both studies, seronconversion rates were unexpectedly low to poliovirus type 1 after mOPV1 or tOPV given at birth but high for all formulations of mOPV1 given at age 30 days. The cause for low immunogenicity of OPV at birth in India is not known.

New strategies for the elimination of polio from India.

The feasibility of global polio eradication is being questioned as a result of continued transmission in a few localities that act as sources for outbreaks elsewhere. Perhaps the greatest challenge is in India, where transmission has persisted in Uttar Pradesh and Bihar despite high coverage with multiple doses of vaccine. We estimate key parameters governing the seasonal epidemics in these areas and show that high population density and poor sanitation cause persistence by not only facilitating transmission of poliovirus but also severely compromising the efficacy of the trivalent vaccine. We analyze strategies to counteract this and show that switching to monovalent vaccine may finally interrupt virus transmission.

Polio control after certification: major issues outstanding.

Now that the global eradication of wild poliovirus is almost within sight, planning for the post-certification era is becoming a priority issue. It is agreed that a stockpile of appropriate polio vaccines will need to be established, and a surveillance and response capacity will need to be maintained, in order to protect the world against any possible future outbreaks attributable either to the persistence of wild poliovirus or vaccine-derived polioviruses (VDPVs) or to the unintentional or intentional release of poliovirus from a laboratory or vaccine store. Although it has been suggested that the stockpile should consist of monovalent oral poliovirus vaccine (mOPV), many questions remain concerning its nature, financing, management, and use--in particular, because of uncertainties over future national vaccination policies, and over the availability of different vaccines, after the certification of wild poliovirus eradication. There are further uncertainties concerning the possible role and efficacy of inactivated poliovirus vaccine (IPV) used either routinely or in outbreak control in low-hygiene settings, the potential for rapid geographical spread of polioviruses should an outbreak occur after certification, and the risks inherent in introducing additional oral polio vaccine (OPV) viruses into populations in which the vaccine coverage and prevalence of immunity have declined, and which may thus favour the spread of VDPVs. Given these important gaps in knowledge, no country should discontinue polio vaccination until a coordinated policy for the post-certification era has been developed and the recommended measures have been put in place.