Antigenic and immunogenic properties of inactivated polio vaccine made from Sabin strains

Inactivated polio vaccine (IPV) was prepared with the Sabin strains, normally used for the attenuated live vaccine. The vaccine was characterized with respect to its antigenicity as determined by ELISA and biosensor analysis and its immunogenicity in rats. Compared with the vaccine prepared with virulent strains (Mahoney, MEF and Saukett) some distinct differences were found with regard to the interaction with glass vials (types 1 and 2) and antigenicity (type 3). The most profound difference however, was the immunogenicity of types 1 and 2. Standardized on the amount of virus, type 1 Sabin-IPV was about 3 times more immunogenic as compared to Mahoney-IPV. The immunogenicity of type 2 Sabin-IPV on the other hand was reduced approximately 10-fold, compared to MEF-IPV. Type 3 Sabin and Saukett IPV were comparable in immunogenicity but differences in antigenicity were evident. The lack of correlation between antigenicity and immunogenicity demonstrate that current IPV standards are not suitable to quantify IPV made from Sabin strains. The results indicate that future Sabin-IPV vaccines may have to contain virus amounts that are very different as compared to current IPV vaccines.     

Safety and immunogenicity of inactivated poliovirus vaccine based on Sabin strains with and without aluminum hydroxide: A phase I trial in healthy adults

Background

An inactivated poliovirus vaccine (IPV) based on attenuated poliovirus strains (Sabin-1, -2 and -3) was developed for technology transfer to manufacturers in low- and middle income countries in the context of the Global Polio Eradication Initiative.

Method

Safety and immunogenicity of the Sabin-IPV was evaluated in a double-blind, randomized, controlled, phase I ‘proof-of-concept’ trial. Healthy male adults received a single intramuscular injection with Sabin-IPV, Sabin-IPV adjuvanted with aluminum hydroxide or conventional IPV. Virus-neutralizing titers against both Sabin and wild poliovirus strains were determined before and 28 days after vaccination.

Results

No vaccine-related serious adverse events were observed, and all local and systemic reactions were mild or moderate and transient. In all subjects, an increase in antibody titer for all types of poliovirus (both Sabin and wild strains) was observed 28 days after vaccination.

Conclusion

Sabin-IPV and Sabin-IPV adjuvanted with aluminum hydroxide administered as a booster dose were equally immunogenic and safe as conventional IPV. EudraCTnr: 2010-024581-22, NCT01708720.     

sIPV process development for costs reduction

Polio is expected to be eradicated within only a few years from now. Upon polio eradication, the use of oral polio vaccines, which can cause circulating and virulent vaccine derived polio viruses, will be stopped. From this moment onwards, inactivated polio vaccines (IPV) will be used for worldwide vaccination against polio. An increased demand for IPV is thus anticipated. As a result, process development studies regarding the IPV production process, developed in the 1960s, have intensified. Studies on yield optimization aiming at costs reduction as well as the use of alternative polio viruses, which are more biosafe for manufacturing, are actual. Here our strategy to setup a new IPV production process using attenuated Sabin polio virus strains is presented. Moreover, aspects on reduction of the costs of goods and the impact of process optimization on sIPV costs are reviewed.     

End phase challenges of poliomyelitis eradication programme realization

The progress of poliomyelitis eradication programme realization, the implementation schedule and strategies for the future, are summarised based on publications of the World Health Organisation. During the following two years wild poliovirus strains should be globally eradicated. This means that potentially in 2010 the global eradication of wild polioviruses will be certified. To eradicate poliomyelitis, cessation of the oral polio vaccine (OPV) is necessary, since the vaccine strains produce cases of vaccine-associated paralytic poliomyelitis (VAPP) and cases of poliomyelitis caused by circulating vaccine-derived poliovirus (cVDPV). However, the WHO plan to stop immunization with OPV and the immunization with inactivated polio vaccine (IPV) shortly after, is alarming in the present situation. The article describes the measures undertaken to prevent or minimise the risk of reintroduction of wild poliovirus strains, which is potentially associated with WHO plan of action.     

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].     

Polio vaccines: WHO position paper,March 2016–recommendations

This article presents the World Health Organization’s (WHO) recommendations on the use of polio vaccine excerpted from the WHO position paper on polio vaccines – March 2016, published in the Weekly Epidemiological Record [1]. This position paper on polio vaccines replaces the 2014 WHO position paper [2]. The 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) [3].Footnotes to this paper provide a number of core references including references to grading tables that assess the quality of the scientific evidence, and to the evidence-to-recommendation table. In accordance with its mandate to provide guidance to Member States on health policy matters, WHO issues a series of regularly updated position papers on vaccines and combinations of vaccines against diseases that have an international public health impact. These papers are concerned primarily with the use of vaccines in large-scale immunization programmes; they summarize essential background information on diseases and vaccines, and conclude with WHO’s current position on the use of vaccines in the global context. This position paper reflects the global switch from trivalent to bivalent OPV which took place in April 2016. Recommendations on the use of polio vaccines have been discussed on multiple occasions by SAGE, most recently in October 2016; evidence presented at these meetings can be accessed at: http://www.who.int/immunization/sage/previous/en/index.html.     

Safety and immunogenicity of a primary series of Sabin-IPV with and without aluminum hydroxide in infants

Background

An inactivated poliovirus vaccine (IPV) based on attenuated poliovirus strains (Sabin-1, -2 and -3) was developed for technology transfer to manufacturers in low- and middle-income countries in the context of the global polio eradication initiative.

Method

Safety and immunogenicity of Sabin-IPV (sIPV) was evaluated in a double-blind, randomized, controlled, dose-escalation trial in the target population. Healthy infants (n = 20/group) aged 56–63 days, received a primary series of three intramuscular injections with low-, middle- or high-dose sIPV with or without aluminum hydroxide or with the conventional IPV based on wild poliovirus strains (wIPV). Virus-neutralizing titers against both Sabin and wild poliovirus strains were determined before and 28 days after three vaccinations.

Results

The incidence of local and systemic reactions was comparable with the wIPV. Seroconversion rates after three vaccinations were 100% for type 2 and type 3 polioviruses (both Sabin and wild strains) and 95–100% for type 1 polioviruses. Median titers were high in all groups. Titers were well above the log₂(titer) correlated with protection (=3) for all groups. Median titers for Sabin-2 were 9.3 (range 6.8–11.5) in the low-dose sIPV group, 9.2 (range 6.8–10.2) in the low-dose adjuvanted sIPV group and 9.8 (range 5.5–15.0) in the wIPV group, Median titers against MEF-1 (wild poliovirus type 2) were 8.2 (range 4.8–10.8) in the low-dose sIPV group, 7.3 (range 4.5–10.2) in the low-dose adjuvanted Sabin-IPV group and 10.3 (range 8.5–17.0) in the wIPV group. For all poliovirus types the median titers increased with increasing dose levels.

Conclusion

sIPV and sIPV adjuvanted with aluminum hydroxide were immunogenic and safe at all dose levels, and comparable with the wIPV.EudraCTnr: 2011-003792-11, NCT01709071.     

灭活脊髓灰质炎病毒疫苗在中国应用的咨询意见调查

目的从扩大免疫规划（Expanded Program on Immunization,EPI）专家认知,来探讨灭活脊髓灰质炎（脊灰）病毒疫苗（Inactivated Poliovirus Vaccine,IPV）在中国应用的相关问题,为制定脊灰疫苗免疫策略提供参考。方法以人口数多和疫苗需求量大为原则,在全国范围内选取7个省（自治区）,对30名EPI专家进行开放式问卷调查。结果50％的调查对象希望在2015年国家能将IPV纳入EPI,与世界卫生组织提出的{2013～2018年消灭脊灰终结战略计划》时间进度表同步,专家们一致认同在保证疫苗质量的前提下,应尽可能地降低疫苗成本,IPV可接受价格中位数为20元／剂（范围5～50元／剂）。实现IPV国产化势在必行,卫生行政等政府部门应尽快明确中国脊灰疫苗免疫策略和使用时间进度表,疾病预防控制中心依据卫生行政部门制定的免疫策略提供技术指导和支持,疫苗生产企业应加快IPV的研发、生产和上市。结论EPI专家一致赞同随着全球消灭脊灰的进程,中国逐步引入IPV是大势所趋。     

An inactivated poliovirus vaccine using Sabin strains produced on the serum-free PER.C6® cell culture platform is immunogenic and safe in a non-human primate model

BackgroundThe World Health Organization recommends the development of affordable next-generation inactivated poliovirus vaccines (IPV) using attenuated poliovirus Sabin strains. Previously, we introduced a novel PER.C6® cell culture platform, which allows for high yield production of an affordable trivalent Sabin IPV vaccine.MethodsImmunogenicity and safety of this novel PER.C6®-based Sabin-IPV (sIPV) was assessed in rats and non-human primates (NHPs). NHPs received one of four different dose dilutions vaccine according to current human schedule (three prime-immunizations and one boost immunization). For comparison, NHPs received commercially available reference Salk IPV or sIPV.ResultsDose-dependent immunogenicity and good tolerability was observed for the PER.C6®-based sIPV formulations in rats and NHPs. In NHPs, the lowest tested dose that induced anti-Sabin virus-neutralizing antibody titers that were non-inferior to commercial sIPV after three immunizations was 5-7.5-25 D-antigen units for type 1, 2 and 3 respectively.DiscussionPER.C6®-based sIPV induced comparable immunogenicity to commercial Salk IPV and sIPV vaccines in NHPs. Together with the absence of any preclinical safety signals, these data warrant further testing in clinical trials. sIPV produced on the PER.C6® cell platform could be one solution to the need for an affordable and immunogenic IPV to achieve and maintain global polio eradication.     

Characterization and standardization of Sabin based inactivated polio vaccine: proposal for a new antigen unit for inactivated polio vaccines

GMP-batches of Sabin-IPV were characterized for their antigenic and immunogenic properties. Antigenic fingerprints of Sabin-IPV reveal that the D-antigen unit is not a fixed amount of antigen but depends on antibody and assay type. Instead of the D-antigen unit we propose standardization of IPV based on a combination of protein amount for dose and D-antigenicity for quality of the vaccine. Although Sabin-IPV type 2 is less immunogenic than regular wild type IPV type 2, the immunogenicity (virus neutralizing titers) per microgram antigen for Sabin-IPV type 2 is in the same order as for wild type serotypes 1 and 3. The latter observations are in line with data from human trials. This suggests that a higher dose of Sabin-IPV type 2 to compensate for the lower rat immunogenicity may not be necessary.     

Polio endgame: Lessons for the global rotavirus vaccination program

Poliovirus and rotavirus share notable similarities. Although rotavirus is not amenable to eradication because of animal reservoirs, live, attenuated oral vaccines have been the bedrock of both prevention and control programs, providing intestinal and humoral immunity. Both programs have also encountered safety concerns and suboptimal immune responses to oral vaccines in low-income settings that have been challenges, prompting the search for alternative solutions. In this paper, we review the progress made by polio prevention and eradication efforts over the past six decades. Specifically, we discuss the roles of the oral polio vaccine (OPV) and the inactivated polio vaccine (IPV) in achieving polio eradication, and explore potential application of these lessons to rotavirus. Recent scientific evidence has confirmed that a combined schedule of IPV and OPV adds synergistic value that may give the polio eradication effort the tools to end all poliovirus circulation worldwide. For rotavirus, oral vaccine is the only currently licensed and recommended vaccine for use in all children worldwide, providing heterologous protection against a broad range of strains. However, parenteral rotavirus vaccines are in the pre-clinical and clinical trial stage and insight from polio provides strong justification for accelerating the development of these vaccines. While challenges for parenteral rotavirus vaccines will need to be addressed, such as achieving protection against a broad range of strains, the principle of combined use of oral and parenteral rotavirus vaccines may provide the necessary humoral and intestinal immunity necessary to close the efficacy gaps between developing and developed countries, therefore controlling rotavirus worldwide. This strategy may also potentially reduce risk of intussusception.     

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.     

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.     

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.     

Global polio eradication: Where are we in Europe and what next?

The world was never so close to reach the polio eradication: only 37 cases notified in 2016 in only three countries, but the game is not yet at the end. The risk of polio outbreaks in the EU is smaller than it has ever been in the past, but it is not so small that we can ignore it. The EU MS must remain alert and plan and prepare for managing polio events or outbreaks because of the possible dire consequences. The IPV only vaccination schedule universally applied in EU has achieved satisfactory coverage, but constantly leaving small accumulating pockets of susceptible individuals. Moreover the IPV only schedule is not an absolute barrier against poliovirus silent transmission as demonstrated in the recent Israel outbreak. The availability of annually revised S.O.P. from WHO GPEI on the identification and response of a polio event, without local poliovirus transmission or a polio outbreak with sustained transmission, helps and challenge EU countries to update their polio national preparedness plans. The EU/EEA area, in fact, is a peculiar area regarding the polio risk both for its vaccination policy, the large polio vaccines manufactures and the constant immigration from areas at polio high risk, but also EU include cultural and financial potentials crucial to sustain the polio end game strategy and reach the benefit of a world without polio risk. Poliovirus eradication will continue to be challenged as long as there is the worldwide presence of polioviruses in laboratories and vaccine production plants. Most of the world’s OPV vaccines are produced in the EU and many laboratories and research centers store and handle polio viruses. EU Member States are engaged actively in implementing the poliovirus biocontainment plans that are part of the polio eradication strategy and to certify the destruction of poliovirus strains and potentially contaminated biological materials.     

后脊髓灰质炎时代我国应用赛宾株灭活脊髓灰质炎疫苗免疫的可行性

在所有国家被证实全部阻断了脊髓灰质炎(脊灰)野病毒传播后,全球将停止使用口服脊灰减毒活疫苗(Oral Poliomyelitis Attenuated Live Vaccine,OPV)免疫,进入后脊灰时代。为此,世界卫生组织(WHO)提出了届时全面停止OPV的使用,并同步开始灭活脊灰病毒疫苗(Inactivated Poliovirus Vaccine,IPV)的免疫,发展中国家更应考虑应用廉价的赛宾(Sabin)株IPV(sIPV)免疫,直至最终根除脊灰。然而目前全球尚无开发成功的sIPV上市。现介绍WHO推荐的这一免疫策略,分析全球sIPV的研发现状,从免疫策略、免疫程序、生产技术、疫苗供应等方面探讨我国应用sIPV免疫的可行性。鉴于这些可行性,我国应尽快推进sIPV的研发进程,为脊灰免疫策略的调整、实施做好准备。     

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.     

Poliomyelitis: eradication in sight.

Eradication of poliomyelitis most likely will occur. In fact, it is almost gone from the Western Hemisphere. Health workers in Sweden, Finland, and the Netherlands routinely vaccinate almost all children with the inactivated poliovaccines (IPV). Despite good vaccination coverage, polio can still occur. For example, in 1978-1979, polio outbreaks occurred among people of closely knit interconnected religious groups in the Netherlands. The virulent type 1 poliovirus was imported from the Middle East and spread to related religious groups in Canada and U.S. Further, in 1984-1985, Finland experienced 10 polio cases. A wild type 3 variant was responsible. An outbreak in 1988 in Israel occurred among young adults who, although received the oral polio vaccine (OPV) as infants, did not receive booster doses. Thus they had an age related deficit in immunity against the wild virus. 6 countries in the Western Pacific Region were able to control polio by 1980, but wild type polioviruses were ubiquitous in 5 other countries in this region and infections were either asymptomatic or unrecognized. They could not control polio by 1980 and just recently able to exert some control. OPV induces serum antibodies, intestinal resistance, and rapid enduring immunity. Also it is easy to administer and inexpensive. Risk of paralytic polio with OPV is 1/1 million vaccinated infants. WHO advises that newborns should be immunized with OPV at the same time as BCG to protect them from polio and to reduce the transmission of wild polioviruses during infancy and childhood. Further many countries have incorporated OPV into routine immunization schedules, but can be difficult in developing countries with limited cold chain capabilities. While some developing countries host periodic mass OPV immunization campaigns. At proper doses, IPV imparts humoral immunity and can be incorporated into other injectable pediatric vaccines (e.g., DPT). Some countries use both IPV and OPV.     

WHO influenza vaccine technology transfer initiative: role and activities of the Technical Advisory Group

In May 2006, the WHO published a Global Pandemic Influenza Action Plan. A significant part of that plan involves the transfer of technology necessary to build production capacity in developing countries. The WHO influenza technology transfer initiative has been successful. Clearly the relatively small WHO investments made in these companies to develop their own influenza vaccine production facilities have had quite dramatic results. A few companies are already producing large amounts of influenza vaccine. Others will soon follow. Whether they are developing egg-based or planning non-egg based influenza vaccine production, all companies are optimistic that their efforts will come to fruition.     

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.