Inactivated Polio Vaccine (IPV): A strong candidate vaccine for achieving global polio eradication program

In this article, we will present an update about current status of inactivated poliovirus vaccine (IPV) and we will also discuss general concerns about inactivated polio vaccine (IPV) which are under discussion in scientific community about various aspects of IPV and at the end of this article, we will give our conclusions about possible universal use of IPV.     

A mucosal adjuvant for the inactivated poliovirus vaccine

The eradication of poliovirus from the majority of the world has been achieved through the use of two vaccines: the inactivated poliovirus vaccine (IPV) and the live-attenuated oral poliovirus vaccine (OPV). Both vaccines are effective at preventing paralytic poliomyelitis, however, they also have significant differences. Most importantly for this work is the risk of revertant virus from OPV, the greater cost of IPV, and the low mucosal immunity induced by IPV. We and others have previously described the use of an alphavirus-based adjuvant that can induce a mucosal immune response to a co-administered antigen even when delivered at a non-mucosal site. In this report, we describe the use of an alphavirus-based adjuvant (GVI3000) with IPV. The IPV-GVI3000 vaccine significantly increased systemic IgG, mucosal IgG and mucosal IgA antibody responses to all three poliovirus serotypes in mice even when administered intramuscularly. Furthermore, GVI3000 significantly increased the potency of IPV in rat potency tests as measured by poliovirus neutralizing antibodies in serum. Thus, an IPV-GVI3000 vaccine would reduce the dose of IPV needed and provide significantly improved mucosal immunity. This vaccine could be an effective tool to use in the poliovirus eradication campaign without risking the re-introduction of revertant poliovirus derived from OPV.     

Inactivated poliovirus vaccine and the final stages of poliovirus eradication

The use of the inactivated poliovirus vaccine (IPV) will increase before and probably also after the global eradication of the wild type poliovirus. Before eradication, the switch from the use of oral poliovirus vaccine (OPV) to IPV has been due to the better safety record of IPV. Introduction of IPV in the regular immunisation schedules is made easier by the development of several combination vaccines, including IPV. Maternal antibodies and young age, often considered problematic for early initiation of IPV schedules, did not compromise optimal maintenance of seropositivity during infancy or long-term persisting antibody levels in our studies. OPV-derived, potentially pathogenic and transmissible poliovirus strains, excreted by some individuals for years, may present a problem for a blunt stopping of all polio immunisations after eradication. Our recent results suggest that locally excreted IgA might have a role in the elimination of poliovirus infection in the intestinal tissues.     

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.     

Immunologic memory induced at birth by immunization with inactivated polio vaccine in a reduced schedule

Abstract of inactivated polio vaccine (IPV) of enhanced potency. Following the administration of a second vaccine dose six months later, a considerable proportion of babies responded with neutralizing antibody (NA) to the three poliovirus types. The very rapid occurrence and high antibody titer were indicative of an anamnestic response. Twenty-one infants who still had NA < 1:4 to one-more poliovirus types after the second vaccine dose responded with very high NA values 7–10 days after a supplementary dose of IPV. It appears that IPV of enhanced potency administered at birth is apt to induce immunologic memory, which should provide the basis for protection against paralytic poliomyelitis in case of exposure to wild poliovirus later in life.     

Efficacy of inactivated poliovirus vaccine in India

The immunogenic efficacy of inactivated (Salk) poliovirus vaccine (IPV) was evaluated in infants in India, in view of the high frequency of vaccine failure after immunization with oral (Sabin) poliovirus vaccine (OPV). A total of 150 infants, aged 6-45 weeks, were given 3 doses of IPV, with intervals of 4 or 8 weeks between doses. The effect on the antibody response of child''s age, presence of maternal antibody before immunization, and interval between doses was assessed. The overall seroconversion rates to poliovirus types 1, 2, and 3 were 99%, 89%, and 91%, respectively. Seroconversion rates to types 2 and 3, and antibody titres to types 1 and 2, were higher (i) in infants given vaccine doses at 8-week intervals and (ii) in those without detectable maternal antibody. The seroconversion rates in infants without maternal antibody, who were given IPV at 8-week intervals, were 100%, 100%, and 96.2% to poliovirus types 1, 2, and 3, respectively. Thus the immunogenic efficacy of IPV was found to be satisfactory.     

Development and introduction of inactivated poliovirus vaccines derived from Sabin strains in Japan

During the endgame of global polio eradication, the universal introduction of inactivated poliovirus vaccines is urgently required to reduce the risk of vaccine-associated paralytic poliomyelitis and polio outbreaks due to wild and vaccine-derived polioviruses. In particular, the development of inactivated poliovirus vaccines (IPVs) derived from the attenuated Sabin strains is considered to be a highly favorable option for the production of novel IPV that reduce the risk of facility-acquired transmission of poliovirus to the communities. In Japan, Sabin-derived IPVs (sIPVs) have been developed and introduced for routine immunization in November 2012. They are the first licensed sIPVs in the world. Consequently, trivalent oral poliovirus vaccine was used for polio control in Japan for more than half a century but has now been removed from the list of vaccines licensed for routine immunization. This paper reviews the development, introduction, characterization, and global status of IPV derived from attenuated Sabin strains.     

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.     

Safety and immunogenicity of a booster dose of inactivated poliovirus vaccine produced in vero-cells

Statens Serum Institut has developed a new vero-cell culturing technique for the manufacturing of inactivated poliovirus vaccine (IPV). This technique implies that the cultivation of cells and poliovirus is performed in a medium free of materials of animal origin and free of antibiotics. In a double-blind randomised clinical trial, IPV(vero) manufactured by this new technique was compared to conventionally produced IPV(mkc). One hundred and twenty-nine (129) healthy adult volunteers were given booster vaccinations of IPV(vero) (65) or IPV(mkc) (64). Both vaccines were well tolerated and resulted in excellent booster responses. No statistically significant differences were seen between the study groups.     

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.     

Lack of immune interference between inactivated polio vaccine and inactivated rotavirus vaccine co-administered by intramuscular injection in two animal species

A parenteral inactivated rotavirus vaccine (IRV) in development could address three problems with current live oral rotavirus vaccines (ORV): their lower efficacy in low and middle-income countries (LMICs), lingering concerns about their association with intussusception, and their requirement for a separate supply chain with large volume cold storage. Adding a new parenteral IRV to the current schedule of childhood immunizations would be more acceptable if it could be combined with another injectable vaccine such as inactivated polio vaccine (IPV). Current plans for polio eradication call for phasing out oral polio vaccine (OPV) and transitioning to IPV, initially in LMICs as a single dose booster after two doses of OPV and ultimately as a two dose schedule. Today in many LMICs, IPV is administered as a standalone vaccine, which involves a separate cold chain and is relatively costly. We therefore tested in two animal models formulations of IPV with IRV to determine whether co-administration might interfere with the immune response to each product and spare antigen dose for both vaccines. Our results demonstrate that IRV when adjuvanted with alum and administered alone or in combination with IPV did not impair the immune responses to either rotavirus or poliovirus serotypes 1, 2 and 3. Similarly, IPV when formulated and administered alone or together with IRV induced comparable levels of neutralizing antibody to poliovirus type 1, 2 and 3. Furthermore, comparable antibody titers were observed in animals vaccinated with low, middle or high dose of IPV or IRV in combination. This dose sparing and the lack of interference between IPV and IRV administered together represent another step to support the further development of this novel combination vaccine for children.     

脊髓灰质炎疫苗应用现状及免疫策略进展

1988年,全球消灭脊髓灰质炎（脊灰）倡议行动启动以来,取得了重大进展。2012年,全球报告脊灰223例,较2011年减少〉60%,本土脊灰流行国家减少为尼日利亚、巴基斯坦和阿富汗,脊灰野病毒（Wild Poliovirus,WPV）病例数下降到历史最低水平。但WPV传播仍未被阻断,无脊灰国家/地区仍面临输入WPV的风险。同时,有些国家正面临使用口服脊灰减毒活疫苗（Oral Poliomyelitis Attenuated Live Vaccine,OPV）所致疫苗衍生脊灰病毒的风险。目前,不同国家/地区评估各自的脊灰发病风险,依据OPV、脊灰病毒灭活疫苗（Inactivated Poliovirus Vaccine,IPV）的风险和收益,不同国家/地区采用不同的免疫策略：仅使用IPV、序贯使用IPV/OPV和仅使用OPV。2013年,世界卫生组织《全球消灭脊灰终结战略计划》中提出,2014年全球阻断WPV传播,2015年所有国家应至少使用1剂IPV,停用OPV中的Ⅱ型组分;2018年完成消灭WPV证实后,停用OPV。现对OPV和IPV的应用现状以及免疫策略进行简述。     

Cost-effectiveness analysis of changing from live oral poliovirus vaccine to inactivated poliovirus vaccine in Australia

OBJECTIVE: Estimate the economic impact of introducing inactivated poliovirus vaccine (IPV) into the Australian childhood immunisation schedule to eliminate vaccine-associated paralytic poliomyelitis (VAPP). METHODS: Cost-effectiveness of two different four-dose IPV schedules (monovalent vaccine and IPV-containing combination vaccine) compared with the current four-dose oral poliovirus vaccine (OPV) schedule for Australian children through age six years. Model used estimates of VAPP incidence, costs, and vaccine utilisation and price obtained from published and unpublished sources. Main outcome measures were total costs, outcomes prevented, and incremental cost-effectiveness, expressed as net cost per case of VAPP prevented. RESULTS: Changing to an IPV-based schedule would prevent 0.395 VAPP cases annually. At $20 per dose for monovalent vaccine and $14 per dose for the IPV component in a combination vaccine, the change would incur incremental, annual costs of $19.5 million ($49.3 million per VAPP case prevented) and $6.7 million ($17.0 million per VAPP case prevented), respectively. Threshold analysis identified break-even prices per dose of $1 for monovalent and $7 for combination vaccines. CONCLUSIONS: Introducing IPV into the Australian childhood immunisation schedule is not likely to be cost-effective unless it comes in a combined vaccine with the IPV-component price below $10. IMPLICATIONS: More precise estimates of VAPP incidence in Australia and IPV price are needed. However, poor cost-effectiveness will make the decision about switching from OPV to IPV in the childhood schedule difficult.     

首剂IPV纳入免疫规划后儿童家长的认知及态度分析

目的了解首剂脊灰活疫苗(IPV)纳入免疫规划后儿童家长的认知及态度,为制定脊灰疫苗免疫策略调整后的实施措施提供参考。方法对2016年7—12月白云街道社区卫生服务中心预防接种门诊接种脊灰疫苗儿童的家长开展问卷调查,并对在此期间参加妈妈班的家长进行个案访谈。结果本次共调查了532人,95.86%的家长知道脊灰减毒活疫苗(糖丸),76.88%认为糖丸是不安全的疫苗,21.43%的家长知道首剂IPV纳入免疫规划政策,16.73%的家长知道2价脊灰与糖丸的区别,81.39%的家长愿意按IPV+b OPV程序接种。多数家长表示赞同首针接种IPV的免疫策略。结论首剂IPV纳入免疫规划后多数家长不了解首针接种脊灰灭活疫苗的免疫策略及其意义,担心疫苗安全问题,建议进一步加强脊灰转换策略相关知识的宣传工作。     

Evaluation of vaccine derived poliovirus type 2 outbreak response options: A randomized controlled trial,Karachi, Pakistan

BackgroundOutbreaks of circulating vaccine derived polioviruses type 2 (cVDPV2) remain a risk to poliovirus eradication in an era without live poliovirus vaccine containing type 2 in routine immunization. We evaluated existing outbreak response strategies recommended by the World Health Organization (WHO) for control of cVDPV2 outbreaks.MethodsSeronegative children for poliovirus type 2 (PV2) at 22 weeks of life were assigned to one of four study groups and received respectively (1) one dose of trivalent oral poliovirus vaccine (tOPV); (2) monovalent OPV 2 (mOPV2); (3) tOPV together with a dose of inactivated poliovirus vaccine (IPV); or (4) mOPV2 with monovalent high-potency IPV type 2. Stool and blood samples were collected and assessed for presence of PV2 (stool) and anti-polio antibodies (sera).ResultsWe analyzed data from 265 children seronegative for PV2. Seroconversion to PV2 was achieved in 48, 76, 98 and 100% in Groups 1–4 respectively. mOPV2 was more immunogenic than tOPV alone (p < 0.001); and OPV in combination with IPV was more immunogenic than OPV alone (p < 0.001). There were 33%, 67%, 20% and 43% PV2 excretors in Groups 1–4 respectively. mOPV2 resulted in more prevalent shedding of PV2 than when tOPV was used (p < 0.001); and tOPV together with IPV resulted in lower excretion of PV2 than tOPV alone (p = 0.046).ConclusionmOPV2 was a more potent vaccine than tOPV. Adding IPV to OPV improved immunological response; adding IPV also seemed to have shortened the duration of PV2 shedding. mIPV2 did not provide measurable improvement of immune response when compared to conventional IPV. WHO recommendation to use mOPV2 as a vaccine of first choice in cVDPV2 outbreak response was supported by our findings.Clinical Trial registry number: NCT02189811.     

Polio vaccination coverage and seroprevalence of poliovirus antibodies after the introduction of inactivated poliovirus vaccines for routine immunization in Japan

In Japan, the oral poliovirus vaccine (OPV) was changed to 2 types of inactivated poliovirus vaccine (IPV), the standalone conventional IPV (cIPV) and the Sabin-derived IPV combined with diphtheria-tetanus-acellular pertussis vaccine (DTaP-sIPV), for routine immunization in 2012. We evaluated polio vaccination coverage and the seroprevalence of poliovirus antibodies using data from the National Epidemiological Surveillance of Vaccine-Preventable Diseases (NESVPD) from 2011 to 2015. Several years before the introduction of IPV in 2012, OPV administration for children was refused by some parents because of concerns about the risk of vaccine-associated paralytic poliomyelitis. Consequently, in children aged <1?years who were surveyed in 2011–2012, polio vaccination coverage (45.0–48.8%) and seropositivity rates for poliovirus (type 1: 51.7–65.9%, type 2: 48.3–53.7%, and type 3: 15.0–29.3%) were decreased compared to those surveyed in 2009. However, after IPV introduction, the vaccination coverage (95.5–100%) and seropositivity rates (type 1: 93.2–96.6%, type 2: 93.1–100%, and type 3: 88.6–93.9%) increased among children aged <1?years in 2013–2015. In particular, seropositivity rates and geometric mean titers (GMTs) for poliovirus type 3 in <5-year-old children who received 4 doses of IPV (98.5% and 247.4, respectively) were significantly higher than in those who received 2 doses of OPV (72.5% and 22.9, respectively). Furthermore, in <5-year-old children who received 4 doses of either DTaP-sIPV or cIPV, the seropositivity rates and the GMTs for all 3 types of poliovirus were similarly high (96.5–100% and 170.3–368.8, respectively). Our findings from the NESVPD demonstrate that both the vaccination coverage and seropositivity rates for polio remained high in children after IPV introduction.     

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.     

不同序贯程序的脊髓灰质炎灭活疫苗和减毒活疫苗的免疫效果研究

目的 评价脊髓灰质炎灭活疫苗（IPV）和减毒活疫苗（OPV）不同序贯免疫程序的免疫效果。方法 选取月龄≥2月的婴儿,分为1剂IPV和2剂OPV序贯组(I - O - O组)、2剂IPV和1剂OPV序贯组(I - I - O组)、IPV全程(I - I - I组)和OPV全程组(O - O - O),分别在2、3、4月龄时各接种1针,检测并比较各组人群血清中脊髓灰质炎中和抗体几何平均滴度（GMT）及抗体阳转率。结果 在完成基础免疫后,I - O - O 组Ⅰ、Ⅱ、Ⅲ型抗体GMT分别为948.78、930.91、955.08;I - I - O组抗体GMT分别为909.43、1 202.34、1 102.83;I - I - I 组GMT分别为333.02、298.56、411.98,O - O - O组抗体GMT分别为814.42、778.27、658.52;差异均有统计学意义;各组3个型别的抗体阳转率均为98％~100％,差异无统计学意义。接种1针IPV后脊髓灰质炎Ⅰ型、Ⅱ型、Ⅲ型中和抗体GMT分别为21.77、30.89、26.46,抗体阳转率分别为84.1％、91.5％、91.5％;接种第2剂IPV后,Ⅰ型、Ⅱ型、Ⅲ型中和抗体GMT分别69.42、133.89、212.58,抗体阳转率分别为100.0％、100.0％、99.9％。结论 IPV与OPV序贯接种后,对象产生的脊髓灰质炎中和抗体GMT比单独接种3剂IPV或3剂OPV高;不同序贯程序中,接种2剂IPV后抗体保护率较高。为了使机体产生更高的抗体水平并且避免疫苗相关麻痹病例发生,可采用IPV与OPV序贯程序,并以2剂IPV和1剂OPV的序贯程序为佳。     

以吸附无细胞百日咳-白喉-破伤风疫苗为基础的联合疫苗研究进展

吸附无细胞百日咳疫苗、白喉和破伤风类毒素联合疫苗（Adsorbed Acellular Pertussis Vaccine,Diphtheria Toxoid＆Tetanus Toxoid Combined Vaccine,DTaP）已有30多年的使用历史。将DTaP与乙型肝炎疫苗（Hepatitis B Vaccine,HepB）、脊髓灰质炎灭活疫苗（Inactivated Poliovirus Vaccine,IPV）和b型流行性感冒嗜血杆菌结合疫苗（Haemophilus Influenzae Type b Conjugate Vaccine,Hib）等制备成为联合疫苗使用,可以减少接种剂次,提高受种者的依从性,从而提高疫苗接种率。但是,联合疫苗不是几种疫苗简单地混合,在将DTaP与其他疫苗联合的过程中面临许多技术挑战,如DTaP与Hib联合存在Hib免疫原性降低的问题,DTaP与HepB联合存在免疫程序不统一和HepB免疫持久性的问题,DTaP与IPV联合时,其中的防腐剂柳硫汞会降低IPV的免疫原性的问题等。现就DTaP与这些疫苗联合时所面临的技术挑战、目前的研究进展和未来发展方向作一综述。     

Adjuvanticity of stearyl tyrosine on inactivated poliovirus vaccine

Preliminary studies of some of the properties of stearyl tyrosine have shown that it is non-toxic, free of adverse reactions at the sites of injection, non-pyrogenic, stable upon storage and easy to sterilize. Formalin inactivated poliovirus vaccine (IPV) adjuvanted with stearyl tyrosine hydrochloride induced significantly higher titres of antibodies in non-human primates, after two injections, than the non-adjuvanted vaccine. Furthermore, the adjuvanted vaccine, even when diluted 1:4, showed consistently higher antibody titres as well as a longer persistence of antibodies than the non-adjuvanted undiluted vaccine. These studies suggest that stearyl tyrosine is an excellent and cost effective adjuvant for IPV. Hence further investigation with this novel synthetic compound would be worthwhile to ascertain its adjuvanticity for IPV in human subjects.