Intradermal fractional dose inactivated polio vaccine: a review of the literature

Oral polio vaccine (OPV) will likely be insufficient to completely eradicate polio due to its propensity to mutate into neurovirulent forms and its inability to produce adequate immunity in certain areas of the world. Inactivated polio vaccine (IPV), a killed vaccine which therefore cannot mutate, may be more effective than OPV in certain populations, and will likely be required for global polio eradication. However, the high cost of IPV is prohibitive in many areas of the world. Intradermal administration has the potential to lower the dose, and thus the cost, of IPV. This article reviews the clinical studies to date on intradermal fractional dose polio vaccination. We conclude that intradermal IPV vaccination shows potential as a means to reduce the cost and increase the ease of administration of IPV, but that additional research is needed to determine the optimal fractional dose, timing, and role of adjuvants in intradermal IPV vaccination as well as the clinical significance of different antibody titers above the threshold for seroconversion.     

PER.C6 cells as a serum-free suspension cell platform for the production of high titer poliovirus: A potential low cost of goods option for world supply of inactivated poliovirus vaccine

There are two highly efficacious poliovirus vaccines: Sabin's live-attenuated oral polio vaccine (OPV) and Salk's inactivated polio vaccine (IPV). OPV can be made at low costs per dose and is easily administrated. However, the major drawback is the frequent reversion of the OPV vaccine strains to virulent poliovirus strains which can result in Vaccine Associated Paralytic Poliomyelitis (VAPP) in vaccinees. Furthermore, some OPV revertants with high transmissibility can circulate in the population as circulating Vaccine Derived Polioviruses (cVDPVs). IPV does not convey VAPP and cVDPVs but the high costs per dose and insufficient supply have rendered IPV an unfavorable option for low and middle-income countries.     

CpG oligodeoxynucleotides are a potent adjuvant for an inactivated polio vaccine produced from Sabin strains of poliovirus

Poliovirus transmission is controlled globally through world-wide use of a live attenuated oral polio vaccine (OPV). However, the imminence of global poliovirus eradication calls for a switch to the inactivated polio vaccine (IPV). Given the limited manufacturing capacity and high cost of IPV, this switch is unlikely in most developing and undeveloped countries. Adjuvantation is an effective strategy for antigen sparing. In this study, we evaluated the adjuvanticity of CpG oligodeoxynucleotides (CpG-ODN) for an experimental IPV produced from Sabin strains of poliovirus. Our results showed that CpG-ODN, alone or in combination with alum, can significantly enhance both the humoral and cellular immune responses to IPV in mice, and, consequently, the antigen dose could be reduced substantially. Therefore, our study suggests that the global use of IPV could be facilitated by using CpG-ODN or other feasible adjuvants.     

Cost analysis of post-polio certification immunization policies

OBJECTIVE: An analysis was conducted to estimate the costs of different potential post-polio certification immunization policies currently under consideration, with the objective of providing this information to policy-makers. METHODS: We analyzed three global policy options: continued use of oral poliovirus vaccine (OPV); OPV cessation with optional inactivated poliovirus vaccine (IPV); and OPV cessation with universal IPV. Assumptions were made on future immunization policy decisions taken by low-, middle-, and high-income countries. We estimated the financial costs of each immunization policy, the number of vaccine-associated paralytic poliomyelitis (VAPP) cases, and the global costs of maintaining an outbreak response capacity. The financial costs of each immunization policy were based on estimates of the cost of polio vaccine, its administration, and coverage projections. The costs of maintaining outbreak response capacity include those associated with developing and maintaining a vaccine stockpile in addition to laboratory and epidemiological surveillance. We used the period 2005-20 as the time frame for the analysis. FINDINGS: OPV cessation with optional IPV, at an estimated cost of US$ 20,412 million, was the least costly option. The global cost of outbreak response capacity was estimated to be US$ 1320 million during 2005-20. The policy option continued use of OPV resulted in the highest number of VAPP cases. OPV cessation with universal IPV had the highest financial costs, but it also had the least number of VAPP cases. Sensitivity analyses showed that global costs were sensitive to assumptions on the cost of the vaccine. Analysis also showed that if the price per dose of IPV was reduced to US$ 0.50 for low-income countries, the cost of OPV cessation with universal IPV would be the same as the costs of continued use of OPV. CONCLUSION: Projections on the vaccine price per dose and future coverage rates were major drivers of the global costs of post-certification polio immunization. The break-even price of switching to IPV compared with continuing with OPV immunizations is US$ 0.50 per dose of IPV. However, this doses not account for the cost of vaccine-derived poliovirus cases resulting from the continued use of OPV. In addition to financial costs, risk assessments related to the re-emergence of polio will be major determinants of policy decisions.     

Long-term evaluation of mucosal and systemic immunity and protection conferred by different polio booster vaccines

Oral polio vaccine (OPV) and Inactivated Polio Vaccine (IPV) have distinct advantages and limitations. IPV does not provide mucosal immunity and introduction of IPV to mitigate consequences of circulating vaccine-derived polio virus from OPV has very limited effect on transmission and OPV campaigns are essential for interrupting wild polio virus transmission, even in developed countries with a high coverage of IPV and protected sewer systems. The problem is magnified in many countries with limited resources. Requirement of refrigeration for storage and transportation for both IPV and OPV is also a major challenge in developing countries. Therefore, we present here long-term studies on comparison of a plant-based booster vaccine, which is free of virus and cold chain with IPV boosters and provide data on mucosal and systemic immunity and protection conferred by neutralizing antibodies.Mice were primed subcutaneously with IPV and boosted orally with lyophilized plant cells containing 1 μg or 25 μg polio viral protein 1 (VP1), once a month for three months or a single booster one year after the first prime. Our results show that VP1-IgG1 titers in single or double dose IPV dropped to background levels after one year of immunization. This decrease correlated with >50% reduction in seropositivity in double dose and <10% seropositivity in single dose IPV against serotype 1. Single dose IPV offered no or minimal protection against serotype 1 and 2 but conferred protection against serotype 3. VP1-IgA titers were negligible in IPV single or double dose vaccinated mice. VP1 antigen with two plant-derived adjuvants induced significantly high level and long lasting VP1-IgG1, IgA and neutralizing antibody titers (average 4.3–6.8 log2 titers). Plant boosters with VP1 and plant derived adjuvants maintained the same level titers from 29 to 400 days and conferred the same level of protection against all three serotypes throughout the duration of this study. Even during period, when no plant booster was given (∼260 days), VP1-IgG1 titers were maintained at high levels. Lyophilized plant cells expressing VP1 can be stored without losing efficacy, eliminating cold chain. Virus-free, cold-chain free vaccine is ready for further clinical development.     

The role of routine polio immunization in the post-certification era

The role of routine vaccination against poliomyelitis for the post-certification era remains an important area for policy decision-making. Two critical decisions need to be taken: first, to continue or discontinue vaccination with the live attenuated oral poliovirus vaccine (OPV); and second, if OPV is to be discontinued, whether vaccination with inactivated poliovirus vaccine (IPV) is needed. Four potential vaccination scenarios can be constructed: stop all polio vaccination; continue with current vaccination policies (OPV, IPV, or sequential schedule); discontinue OPV, but continue IPV universally; or discontinue OPV, but continue IPV in selected countries. All possible scenarios require continued investments in a surveillance and response strategy, including a stockpile of polio vaccine. Continuing vaccination would limit the savings that could be applied to the control of other health priorities. This report reviews the key issues associated with each scenario, highlights the advantages and disadvantages of each scenario, and outlines the major challenges for policy decision-making.     

World wide experience with inactivated poliovirus vaccine

As part of the global poliovirus eradication strategy, oral poliovirus vaccine (OPV) has successfully contributed to reduce polio incidence rates globally. However, because of the OPV-related risks of vaccine associated paralytic poliomyelitis (VAPP) and vaccine-derived polioviruses (VDPVs) OPV cessation is required in order to achieve complete eradication of polio. Inactivated poliovirus vaccine (IPV) is a viable option for incorporation into existing vaccination schedules so as to avoid these risks. Furthermore, the continuation of vaccination with IPV will protect populations in case of re-emergence of wild-type poliovirus from remote locations, laboratory samples, or through bioterrorism. The ability of IPV to prevent poliovirus outbreaks and provide herd protection has been demonstrated in several circumstances and in various settings. This paper reviews clinical experiences with IPV administration and outcomes in various countries in Europe, the Americas, Africa and Asia.     

The cost-effectiveness of alternative polio immunization policies in South Africa

AIMS: To assess the cost-effectiveness of switching from oral polio vaccine (OPV) to inactivated poliovirus vaccine (IPV), or to cease polio vaccination in routine immunization services in South Africa at the time of OPV cessation globally following polio eradication. METHODS: The cost-effectiveness of nine different polio immunization alternatives were evaluated. The costs of introducing IPV in a separate vial as well as in different combination vaccines were estimated, and IPV schedules with 2, 3 and 4 doses were compared with the current 6-dose OPV schedule. Assumptions about IPV prices were based on indications from vaccine manufacturers. The health impact of OPV cessation was measured in terms of vaccine associated paralytic paralysis (VAPP) cases and disability adjusted life years (DALYs) averted. CONCLUSIONS: The use of OPV in routine immunization services is predicted to result in 2.96 VAPP cases in the 2005 cohort. The cost-effectiveness of the different IPV alternatives varies between US$ 740,000 and US$ 7.2 million per VAPP case averted. The costs per discounted DALY averted amount to between US$ 61,000 and US$ 594,000. Among the IPV strategies evaluated, the 2-dose schedule in a 10-dose vial is the most cost-effective option. At the assumed vaccine prices, all IPV options do not appear to be cost-effective in the South African situation. OPV cessation without IPV replacement would result in cost savings of US$ 1.6 million per year compared to the current situation. This is approximately a 9% decrease in the budget for vaccine delivery in South Africa. However, with this option there is a risk (albeit small) of vaccine-derived poliovirus circulating in a progressively susceptible population. For IPV in a single dose vial, the break-even price, at which the costs of IPV delivery equal the current OPV delivery costs, is US$ 0.39.     

Introduction of inactivated polio vaccine (IPV) into the routine immunization schedule of South Africa

South Africa is currently the only country on the African continent using inactivated polio vaccine (IPV) for routine immunization in a sequential schedule in combination with oral polio vaccine (OPV). IPV is a component of an injectable pentavalent vaccine introduced nationwide in April 2009 and administered according to EPI schedule at 6, 10 and 14 weeks with a booster dose at 18 months. OPV is administered at birth and together with the first IPV dose at 6 weeks, which stimulates gut immune system producing a memory IgA response (OPV), followed by IPV to minimize the risk of vaccine associated paralytic polio (VAPP). OPV is also given to all children under 5 years of age as part of regular mass immunizations campaigns. The decision to incorporate IPV into the routine schedule was not based on cost-effectiveness, which it is not. Other factors were taken into account: Firstly, the sequence benefits from the initial mucosal contact with live(vaccine) virus which promotes the IgA response from subsequent IPV, as well as herd immunity from OPV, together with the safety of IPV. Secondly, given the widespread and increasing use of IPV in the developed world, public acceptance of vaccination in general is enhanced in South Africa which is classified as an upper middle income developing country. Thirdly, to address equity concerns because of the growing use of IPV in the private sector. Fourthly, the advent of combination vaccines facilitated the incorporation of IPV into the EPI schedule.     

Poliomyelitis prevention in the United States. Updated recommendations of the Advisory Committee on Immunization Practices (ACIP).

These recommendations of the Advisory Committee on Immunization Practices (ACIP) for poliomyelitis prevention replace those issued in 1997. As of January 1, 2000, ACIP recommends exclusive use of inactivated poliovirus vaccine (IPV) for routine childhood polio vaccination in the United States. All children should receive four doses of IPV at ages 2, 4, and 6-18 months and 4-6 years. Oral poliovirus vaccine (OPV) should be used only in certain circumstances, which are detailed in these recommendations. Since 1979, the only indigenous cases of polio reported in the United States have been associated with the use of the live OPV. Until recently, the benefits of OPV use (i.e., intestinal immunity, secondary spread) outweighed the risk for vaccine-associated paralytic poliomyelitis (VAPP) (i.e., one case among 2.4 million vaccine doses distributed). In 1997, to decrease the risk for VAPP but maintain the benefits of OPV, ACIP recommended replacing the all-OPV schedule with a sequential schedule of IPV followed by OPV. Since 1997, the global polio eradication initiative has progressed rapidly, and the likelihood of poliovirus importation into the United States has decreased substantially. In addition, the sequential schedule has been well accepted. No declines in childhood immunization coverage were observed, despite the need for additional injections. On the basis of these data, ACIP recommended on June 17, 1999, an all-IPV schedule for routine childhood polio vaccination in the United States to eliminate the risk for VAPP. ACIP reaffirms its support for the global polio eradication initiative and the use of OPV as the only vaccine recommended to eradicate polio from the remaining countries where polio is endemic.     

The global introduction of inactivated polio vaccine can circumvent the oral polio vaccine paradox

This literature review identifies the factors that influence the decision to introduce inactivated polio vaccine (IPV) in developing countries as opposed to the policy of vaccine cessation. Attenuated viruses in the oral polio vaccine (OPV) can replicate, revert to neurovirulence and become transmissible circulating vaccine-derived polioviruses (cVDPVs), preventing use of the vaccine in the post-eradication era. This literature review identifies (1) risks of complete cessation of vaccination, (2) barriers and (3) solutions for the introduction of IPV in developing countries. The reviewed literature favours to circumvent the so-called “OPV paradox” by global introduction of IPV.     

Inactivated polio vaccination using a microneedle patch is immunogenic in the rhesus macaque

The phased replacement of oral polio vaccine (OPV) with inactivated polio vaccine (IPV) is expected to significantly complicate mass vaccination campaigns, which are an important component of the global polio eradication endgame strategy. To simplify mass vaccination with IPV, we developed microneedle patches that are easy to administer, have a small package size, generate no sharps waste and are inexpensive to manufacture. When administered to rhesus macaques, neutralizing antibody titers were equivalent among monkeys vaccinated using microneedle patches and conventional intramuscular injection for IPV types 1 and 2. Serologic response to IPV type 3 vaccination was weaker after microneedle patch vaccination compared to intramuscular injection; however, we suspect the administered type 3 dose was lower due to a flawed pre-production IPV type 3 analytical method. IPV vaccination using microneedle patches was well tolerated by the monkeys. We conclude that IPV vaccination using a microneedle patch is immunogenic in rhesus macaques and may offer a simpler method of IPV vaccination of people to facilitate polio eradication.     

Imported vaccine-associated paralytic poliomyelitis--United States, 2005

Paralytic poliomyelitis is rare in the United States because of the success of universal childhood immunization and the Global Polio Eradication Initiative. Poliovirus vaccine was introduced in the 1950s. Since then, the United States has eliminated indigenous wild poliovirus transmission, controlled imported wild poliovirus cases, and, through a vaccine policy change (i.e., from live, attenuated oral polio vaccine [OPV] to inactivated polio vaccine [IPV]), eliminated vaccine-associated paralytic polio (VAPP) cases. The most recent VAPP case occurred in 1999. The primary risk for paralytic polio for U.S. residents is through travel to countries where polio remains endemic or where polio outbreaks are occurring. This report describes the first known occurrence of imported VAPP in an unvaccinated U.S. adult who traveled abroad, where she likely was exposed through contact with an infant recently vaccinated with OPV. This case highlights the previously unrecognized risk for paralytic polio among unvaccinated persons exposed to OPV during travel abroad.     

Economics of polio vaccination in the post-eradication era: should OPV-using countries adopt IPV?

The continued use of oral polio vaccine (OPV) poses a threat to polio virus eradication. Stopping all polio vaccination in the post-certification era is no longer considered to be a practical option. Policy makers agree that OPV use must stop immediately after certification. Therefore, the pragmatic alternative is for the OPV-using countries to switch to IPV. This study estimates the cost of switching to IPV, and the cost-effectiveness of this switch. Using data on the number of polio cases and the number of unvaccinated children in different countries of the world, the risks of polio and polio outbreaks have been calculated. The current cost of routine and intensive OPV immunisation is about US $2143 million in the 148 OPV-using countries. Routine use of IPV in these countries should cost US $1246 million. If the current costs of routine and intensive polio immunisation are considered, adopting IPV to replace OPV will not increase the total global cost. Even if the cost of intensive polio immunisation is ignored, cost-effectiveness ratio of adopting IPV remains less than the average GNI per capita of OPV-using countries. The incremental cost of adopting IPV to replace OPV is relatively low, about US $1 per child per year, and most countries should be able to afford this additional cost.     

Immunogenicity of four doses of oral poliovirus vaccine when co-administered with the human neonatal rotavirus vaccine (RV3-BB)

BackgroundThe RV3-BB human neonatal rotavirus vaccine was developed to provide protection from severe rotavirus disease from birth. The aim of this study was to investigate the potential for mutual interference in the immunogenicity of oral polio vaccine (OPV) and RV3-BB.MethodsA randomized, placebo-controlled trial involving 1649 participants was conducted from January 2013 to July 2016 in Central Java and Yogyakarta, Indonesia. Participants received three doses of oral RV3-BB, with the first dose given at 0–5 days (neonatal schedule) or ~8 weeks (infant schedule), or placebo. Two sub-studies assessed the immunogenicity of RV3-BB when co-administered with either trivalent OPV (OPV group, n = 282) or inactivated polio vaccine (IPV group, n = 333). Serum samples were tested for antibodies to poliovirus strains 1, 2 and 3 by neutralization assays following doses 1 and 4 of OPV.ResultsSero-protective rates to poliovirus type 1, 2 or 3 were similar (range 0.96–1.00) after four doses of OPV co-administered with RV3-BB compared with placebo. Serum IgA responses to RV3-BB were similar when co-administered with either OPV or IPV (difference in proportions OPV vs IPV: sIgA responses; neonatal schedule 0.01, 95% CI −0.12 to 0.14; p = 0.847; infant schedule −0.10, 95% CI −0.21 to −0.001; p = 0.046: sIgA GMT ratio: neonatal schedule 1.23, 95% CI 0.71–2.14, p = 0.463 or infant schedule 1.20, 95% CI 0.74–1.96, p = 0.448).ConclusionsThe co-administration of OPV with RV3-BB rotavirus vaccine in a birth dose strategy did not reduce the immunogenicity of either vaccine. These findings support the use of a neonatal RV3-BB vaccine where either OPV or IPV is used in the routine vaccination schedule.     

Serological response and poliovirus excretion following different combined oral and inactivated poliovirus vaccines immunization schedules

A controlled study was conducted in Karachi, Pakistan to compare humoral and mucosal immune responses against polioviruses in infants who received oral poliovirus vaccine (OPV) at birth and at 6, 10, and 14 weeks according to the Expanded Program on Immunization (EPI) with infants who received either three doses of inactivated poliovirus vaccine (IPV) at 6, 10, and 14 weeks together with OPV or one additional dose of IPV at 14 weeks together, with the last dose of OPV. A total of 1429 infants were enrolled; 24-week serum specimens were available for 898 infants (63%). They all received a challenge dose of OPV type 3 at 24 weeks of age. The addition of three doses of IPV to three doses of OPV induced a significantly higher percentage of seropositive children at 24 weeks of age for polio 1 (97% versus 89%, P<0.001) and polio 3 (98% versus 92%) compared to the EPI schedule. However, the one supplemental dose of IPV at 14 weeks did not increase the serological response at 24 weeks. Intestinal immunity against the challenge dose was similar in the three groups. Combined schedules of OPV and IPV in the form of diphtheria-pertussis-tetanus-IPV vaccine (DPT-IPV) may be useful to accelerate eradication of polio in developing countries.     

Polio eradication in India: some observations

In 1988, the World Health Assembly passed resolution WHA 41.28, which committed the World Health Organization (WHO) to the global eradication of poliomyelitis by the year 2000. In spite of the combined efforts by UNICEF, National Polio Surveillance Project (NPSP), Indian Academy of Pediatrics (IAP) and Rotary International, Polio Free India is still a distant dream.Though oral polio vaccine has succeeded in polio eradication from many countries but there is high incidence of vaccine failure in India.Oral polio vaccine (OPV) has failed to provide full protection to many children who have developed paralytic polio even after taking 10 or more doses of OPV. In some children, OPV has caused paralysis-vaccine associated paralytic polio (VAPP). Number of children developing polio due to vaccine is high and on increase. Reasons for this could be that even immunocompromised children are being administered OPVbecause IPV is not available. Vaccine failure has exaggerated the problem of VAPP. No efforts have been made to find the causes for high incidence of vaccine failure and VAPP.     

Polio vaccines: WHO position paper,January 2014 – Recommendations

This article presents the World Health Organizations (WHO) evidence and recommendations for the use of polio vaccination from the WHO position paper on polio vaccines – January 2014 recently published in the Weekly Epidemiological Record [1]. This position paper summarizes the WHO position on the introduction of at least one dose of inactivated polio vaccine (IPV) into routine immunization schedules as a strategy to mitigate the potential risk of re-emergence of type 2 polio following the withdrawal of Sabin type 2 strains from oral polio vaccine (OPV). The current document replaces the position paper on the use of polio vaccines published in 2010 [2].     

A ten-year experience in control of poliomyelitis through a combination of live and killed vaccines in two developing areas.

We describe a successful program of poliomyelitis control using a combination of killed and live polio vaccines over a 10-year period in two developing areas, the West Bank and Gaza, adjacent to a relatively developed country, Israel. During the 1970s, immunization using live trivalent oral polio vaccine (OPV) in these areas covered more than 90 percent of the infant population. Nevertheless, the incidence of paralytic polio continued to be high, with many cases occurring in fully or partially immunized persons. It was thought that this could be due to interference with OPV take by other enteroviruses present in the environment due to poor sanitary conditions in these areas. A new policy combining five doses of OPV with two doses of inactivated polio vaccine (IPV) was adopted and implemented in 1978. In the 10 years since then, immunization coverage of infants increased to an estimated 95 percent and paralytic poliomyelitis has been controlled, despite exposure to wild poliovirus from neighboring countries including an outbreak in Israel in 1988. This experience suggests that wide coverage using the combination of IPV and OPV is an effective vaccination policy that may make eradication of polio possible even in developing areas.