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.     

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.     

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.     

Immunogenicity and reactogenicity of rhesus rotavirus vaccine given in combination with oral or inactivated poliovirus vaccines and diphtheria-tetanus-pertussis vaccine.

Immunogenicity and reactogenicity of the oral rhesus rotavirus vaccine (RRV) were assessed among 72 infants (6 weeks old) in Lahore, Pakistan, from August to December 1985. Special emphasis was placed on the possible interaction or interference caused by giving RRV at the time infants received their first polio immunization. RRV was given to the infants at the same time as diphtheria-tetanus-pertussis (DTP), oral poliovirus vaccine (OPV), or inactivated poliovirus vaccine (IPV). The immune response to RRV was assessed by plaque-reduction neutralization 3 weeks after immunization and serum immunoglobulin (Ig) G and IgA antibody levels to poliovirus type 1 were tested by enzyme-linked immunosorbent assay (ELISA) after polio immunizations. Of the infants in the group given RRV with OPV, 50% had a two- to four-fold rise in neutralization titre against rotavirus, compared with 22% in the group given RRV with DTP and 20% in the group given RRV and IPV (P less than 0.05). Interference by live oral polio vaccination in the response to RRV seems unlikely. We observed no significant difference in rates of seroconversion of IgG antibodies to poliovirus type 1 among infants aged 18 and 21 weeks who received RRV and OPV (81%), RRV with delayed OPV (67%), or RRV and IPV (59%). Administration of RRV was safe and was not associated with adverse reactions in the 6 weeks old infants. The low rate of seroconversion to rotavirus suggests that a more antigen-rich vaccine or multiple doses of the same vaccine might produce a better immune response.     

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.     

Lower immunity to poliomyelitis viruses in Australian young adults not eligible for inactivated polio vaccine

There are limited long-term data on seroprevalence of neutralising antibody (nAb) to the three poliovirus serotypes following the switch from oral polio vaccine (OPV) to inactivated polio vaccine (IPV). In Australia, combination vaccines containing IPV replaced OPV in late 2005. Using serum and plasma specimens collected during 2012 and 2013, we compared prevalence of nAb to poliovirus type 1 (PV1), type 2 (PV2) and type 3 (PV3) in birth cohorts with differing IPV and OPV eligibility from an Australian population-based sample. In the total sample of 1673 persons aged 12 months to 99 years, 85% had nAb against PV1, 83% PV2 and 67% PV3. In the cohort 12 to <18 years (eligible for 4 OPV doses, last dose 8–14 years prior), a significantly lower proportion had nAb than in the 7 to <12 year cohort (eligible for 3 OPV doses and an IPV booster, last dose 3–8 years prior) for all poliovirus types: [PV1: 87.1% vs. 95.9% (P = 0.01), PV2: 80.4% vs. 92.9% (P = 0.003) and PV3: 38.1% vs. 84.0% (P < 0.0001)]. These data suggest individual-level immunity may be better maintained when an OPV primary schedule is boosted by IPV, and support inclusion of an IPV booster in travel recommendations for young adults who previously received only OPV.     

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.     

Immune response to an intercalated enhanced inactivated polio vaccine/oral polio vaccine programme in Israel: impact on the control of poliomyelitis

A combined enhanced inactivated polio vaccine (EIPV) and oral polio vaccine (OPV) programme was introduced in Israel in 1990, with the purpose of providing a solution to the persistent polio morbidity in spite of a 30 year long OPV programme. The schedule comprised two doses of EIPV administered at the age of 2 and 4 months, intercalated with two doses of OPV at 4 and 6 months, followed by a reinforcing dose with the two vaccines simulltaneously administered at 12 months. The 5-year evaluation of the programme included: the assessment of clinical suspicions of polio, early immune response in successive cohorts administered the new schedule, dynamics of the immune profile in a cohort followed up to the age of 5, and monitoring of wild poliovirus excretion in sewage specimens collected in 25 permanent sites throughout Israel as well as from the Palestinian Authority. No paralytic polio cases associated with a wild or vaccinal poliovirus strain were detected since the introduction of the programme. At the age of 4 months, one week after administration of the second EIPV and first OPV dose, 100% seropositivity and high geometric mean titres (GMTs) of neutralizing antibody (NA) to the three vaccinal and to the wild poliovirus type 1, responsible for the 1988 polio outbreak, were observed. No change in percent of seropositivity occurred between the age of 6 and 12 months. Thirty days after the IPV and OPV reinforcing doses, GMTs to each of the four poliovirus strains were ≥3037. Up to the age of 5, the seropositivity was unchanged. After a 2.5–10-fold decline in the first year following the completion of the programme, GMTs to the three vaccinal and the wild poliovirus strain levelled off at rather high values, considered protective. Between 1990 and 1995, 16 wild poliovirus type 1 strains were isolated in three separate episodes in Gaza Strip sewage and once only in one Israeli site very close to Gaza City. The rapidly established, high and persistent NA titre to the vaccinal and wild poliovirus strains and the presence of immunological memory are indicative of high individual protection throughout the first 5 years of life. The only one-time introduction, without circulation, of a wild poliovirus strain in a single Israeli settlement suggests community protection. The intercalated programme offers a contribution to polio eradication by providing a solution to the primary and secondary failure associated with POV, as well as to the control of vaccine-associated paralytic poliomyelitis.     

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.     

Adjuvants and inactivated polio vaccine: A systematic review

Poliomyelitis is nearing universal eradication; in 2011, there were 650 cases reported globally. When wild polio is eradicated, global oral polio vaccine (OPV) cessation followed by use of universal inactivated polio vaccine (IPV) is believed to be the safest vaccination strategy as IPV does not mutate or run the risk of vaccine derived outbreaks that OPV does. However, IPV is significantly more expensive than OPV. One strategy to make IPV more affordable is to reduce the dose by adding adjuvants, compounds that augment the immune response to the vaccine. No adjuvants are currently utilized in stand-alone IPV; however, several have been explored over the past six decades. From aluminum, used in many licensed vaccines, to newer and more experimental adjuvants such as synthetic DNA, a diverse group of compounds has been assessed with varying strengths and weaknesses. This review summarizes the studies to date evaluating the efficacy and safety of adjuvants used with IPV.     

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.     

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。     

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.     

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.     

Increased potency of an inactivated trivalent polio vaccine with oil-in-water emulsions

The use of inactivated poliovirus vaccines (IPV) will be required to achieve, world-wide eradication of polio. The current expense of IPV is however prohibitive for, some countries, and therefore efforts to decrease the costs of the vaccine are a high, priority. Our results show that the addition of oil-in-water emulsion adjuvants to an, inactivated trivalent poliovirus vaccine are dose-sparing and are capable of enhancing, neutralizing antibody titers in the rat potency model.     

Immune responses after fractional doses of inactivated poliovirus vaccine using newly developed intradermal jet injectors: A randomized controlled trial in Cuba

IntroductionThe World Health Organization recommends that, as part of the new polio endgame, a dose of inactivated poliovirus vaccine (IPV) be introduced by the end of 2015 in all countries using only oral poliovirus vaccine (OPV). Administration of fractional dose (1/5th of full dose) IPV (fIPV) intradermally may reduce costs, but its administration is cumbersome with BCG needle and syringe. We evaluated performance of two newly developed intradermal-only jet injectors and compared the immune response induced by fIPV with that induced by full-dose IPV.MethodsChildren between 12 and 20 months of age, who had previously received two doses of OPV, were enrolled in Camaguey, Cuba. Subjects received a single dose of IPV (either full-dose IPV intramuscularly with needle and syringe or fIPV intradermally administered with one of two new injectors or with BCG needle or a conventional needle-free injector). Serum was tested for presence of poliovirus neutralizing antibodies on day 0 (pre-IPV) and on days 3, 7 and 21 (post-vaccination).ResultsComplete data were available from 74.2% (728/981) subjects. Baseline median antibody titers were 713, 284, and 113 for poliovirus types 1, 2, and 3, respectively. Seroprevalence at study end were similar across the intervention groups (≥94.8%). The immune response induced with one new injector was similar to BCG needle and to the conventional injector; and superior to the other new injector. fIPV induced significantly lower boosting response compared to full-dose IPV. No safety concerns were identified.InterpretationOne of the two new injectors demonstrated its ability to streamline intradermal fIPV administration, however, further investigations are needed to assess the potential contribution of fIPV in the polio endgame plan.     

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.