Concept: Polio vaccine
We examined the introduction of diphtheria-tetanus-pertussis (DTP) and oral polio vaccine (OPV) in an urban community in Guinea-Bissau in the early 1980s.
The WHO recommends complete withdrawal of Oral Polio Vaccine (OPV) Type 2 by April 2016 globally and replacing with at least one dose of Inactivated Poliovirus Vaccine (IPV). However, high-cost, limited supply of IPV, persistent circulating vaccine-derived polioviruses transmission and need for subsequent boosters remain unresolved. To meet this critical need, a novel strategy of a low cost cold-chain free plant-made viral protein 1 (VP1) subunit oral booster vaccine after single IPV dose is reported. Codon optimization of the VP1 gene enhanced expression by 50-fold in chloroplasts. Oral boosting of VP1 expressed in plant cells with plant-derived adjuvants after single priming with IPV significantly increased VP1-IgG1 and VP1-IgA titers when compared to lower IgG1 or negligible IgA titers with IPV injections. IgA plays a pivotal role in polio eradication because of its transmission through contaminated water or sewer systems. Neutralizing antibody titers (~3.17-10.17 log2 titer) and serpositivity (70-90%) against all three poliovirus Sabin serotypes were observed with two doses of IPV and plant-cell oral boosters but single dose of IPV resulted in poor neutralization. Lyophilized plant cells expressing VP1 stored at ambient temperature maintained efficacy and preserved antigen folding/assembly indefinitely, thereby eliminating cold-chain currently required for all vaccines. Replacement of OPV with this booster vaccine and the next steps in clinical translation of FDA approved antigens and adjuvants are discussed. This article is protected by copyright. All rights reserved.
Poliovirus (PV) is the causative agent of poliomyelitis, a crippling human disease known since antiquity. PV occurs in two distinct antigenic forms, D and C, of which only the D form elicits a robust neutralizing response. Developing a synthetically produced stabilized virus-like particle (sVLP)-based vaccine with D antigenicity, without the drawbacks of current vaccines, will be a major step towards the final eradication of poliovirus. Such a sVLP would retain the native antigenic conformation and the repetitive structure of the original virus particle, but lack infectious genomic material. In this study, we report the production of synthetically stabilized PV VLPs in plants. Mice carrying the gene for the human PV receptor are protected from wild-type PV when immunized with the plant-made PV sVLPs. Structural analysis of the stabilized mutant at 3.6 Å resolution by cryo-electron microscopy and single-particle reconstruction reveals a structure almost indistinguishable from wild-type PV3.Despite the success of current vaccination against poliomyelitis, safe, cheap and effective vaccines remain sought for continuing eradication effort. Here the authors use plants to express stabilized virus-like particles of type 3 poliovirus that can induce a protective immune response in mice transgenic for the human poliovirus receptor.
There are currently huge efforts by the World Health Organization and partners to complete global polio eradication. With the significant decline in poliomyelitis cases due to wild poliovirus in recent years, rare cases related to the use of live-attenuated oral polio vaccine assume greater importance. Poliovirus strains in the oral vaccine are known to quickly revert to neurovirulent phenotype following replication in humans after immunisation. These strains can transmit from person to person leading to poliomyelitis outbreaks and can replicate for long periods of time in immunodeficient individuals leading to paralysis or chronic infection, with currently no effective treatment to stop excretion from these patients. Here, we describe an individual who has been excreting type 2 vaccine-derived poliovirus for twenty eight years as estimated by the molecular clock established with VP1 capsid gene nucleotide sequences of serial isolates. This represents by far the longest period of excretion described from such a patient who is the only identified individual known to be excreting highly evolved vaccine-derived poliovirus at present. Using a range of in vivo and in vitro assays we show that the viruses are very virulent, antigenically drifted and excreted at high titre suggesting that such chronic excreters pose an obvious risk to the eradication programme. Our results in virus neutralization assays with human sera and immunisation-challenge experiments using transgenic mice expressing the human poliovirus receptor indicate that while maintaining high immunisation coverage will likely confer protection against paralytic disease caused by these viruses, significant changes in immunisation strategies might be required to effectively stop their occurrence and potential widespread transmission. Eventually, new stable live-attenuated polio vaccines with no risk of reversion might be required to respond to any poliovirus isolation in the post-eradication era.
Poliomyelitis has nearly been eradicated through the efforts of the World Health Organization’s Global Eradication Initiative raising questions on containment of the virus after it has been eliminated in the wild. Most manufacture of inactivated polio vaccines currently requires the growth of large amounts of highly virulent poliovirus, and release from a production facility after eradication could be disastrous; WHO have therefore recommended the use of the attenuated Sabin strains for production as a safer option although it is recognised that they can revert to a transmissible paralytic form. We have exploited the understanding of the molecular virology of the Sabin vaccine strains to design viruses that are extremely genetically stable and hyperattenuated. The viruses are based on the type 3 Sabin vaccine strain and have been genetically modified in domain V of the 5' non-coding region by changing base pairs to produce a cassette into which capsid regions of other serotypes have been introduced. The viruses give satisfactory yields of antigenically and immunogenically correct viruses in culture, are without measurable neurovirulence and fail to infect non-human primates under conditions where the Sabin strains will do so.
Inactivated poliovirus vaccine (IPV) is efficacious against paralytic disease, but its effect on mucosal immunity is debated. We assessed the efficacy of IPV in boosting mucosal immunity. Participants received IPV, bivalent 1 and 3 oral poliovirus vaccine (bOPV), or no vaccine. A bOPV challenge was administered 4 weeks later, and excretion was assessed 3, 7, and 14 days later. Nine hundred and fifty-four participants completed the study. Any fecal shedding of poliovirus type 1 was 8.8, 9.1, and 13.5% in the IPV group and 14.4, 24.1, and 52.4% in the control group by 6- to 11-month, 5-year, and 10-year groups, respectively (IPV versus control: Fisher’s exact test P < 0.001). IPV reduced excretion for poliovirus types 1 and 3 between 38.9 and 74.2% and 52.8 and 75.7%, respectively. Thus, IPV in OPV-vaccinated individuals boosts intestinal mucosal immunity.
Poliomyelitis is a highly infectious disease caused by poliovirus (PV). It can result in paralysis and may be fatal. Integrated global immunisation programmes using live-attenuated oral (OPV) and/or inactivated PV vaccines (IPV) have systematically reduced its spread and paved the way for eradication. Immunisation will continue post-eradication to ensure against reintroduction of the disease, but there are biosafety concerns for both OPV and IPV. These could be addressed by the production and use of virus-free virus-like particle (VLP) vaccines which mimic the ‘empty’ capsids (ECs) normally produced in viral infection. Although ECs are antigenically indistinguishable from mature virus particles, they are less stable and readily convert to an alternative conformation unsuitable for vaccine purposes. Stabilised ECs, expressed recombinantly as VLPs, could be ideal candidate vaccines for a polio-free world. However, although genome-free PV ECs have been expressed as VLPs in a variety of systems, their inherent antigenic instability has proved a barrier to further development. In this study, we have selected thermally-stable ECs of type-1 PV (PV-1). The ECs are antigenically stable at temperatures above the conversion temperature of wild type (wt) virion. We have identified mutations on the capsid surface and internal networks that are responsible for the EC stability. With reference to the capsid structure, we speculate on the roles of these residues in capsid stability and postulate that such stabilised VLPs could be used as novel vaccines.
Because oral polio vaccine has been associated with cases of paralysis, it is essential to discontinue its use after polio eradication has been certified. The first step is a shift from a trivalent OPV to a bivalent one, which requires a multipronged global strategy.
To secure a polio-free world, the live attenuated oral poliovirus vaccine (OPV) will eventually need to be replaced with inactivated poliovirus vaccines (IPV). However, current IPV delivery is less suitable for campaign use than OPV, and more expensive. We are progressing a microarray patch delivery platform, the Nanopatch, as an easy-to-use device to administer vaccines, including IPV. The Nanopatch contains an ultra-high density array (10,000/cm(2)) of short (~230 μm) microprojections that delivers dry coated vaccine into the skin. Here, we compare the relative immunogenicity of Nanopatch immunisation versus intramuscular injection in rats, using monovalent and trivalent formulations of IPV. Nanopatch delivery elicits faster antibody response kinetics, with high titres of neutralising antibody after just one (IPV2) or two (IPV1 and IPV3) immunisations, while IM injection requires two (IPV2) or three (IPV1 and IPV3) immunisations to induce similar responses. Seroconversion to each poliovirus type was seen in 100% of rats that received ~1/40th of a human dose of IPV delivered by Nanopatch, but not in rats given ~1/8th or ~1/40th dose by IM injection. Ease of administration coupled with dose reduction observed in this study suggests the Nanopatch could facilitate inexpensive IPV vaccination in campaign settings.
Sustained and coordinated vaccination efforts have brought polio eradication within reach. Anticipating the eradication of wild poliovirus (WPV) and the subsequent challenges in preventing its re-emergence, we look to the past to identify why polio rose to epidemic levels in the mid-20th century, and how WPV persisted over large geographic scales. We analyzed an extensive epidemiological dataset, spanning the 1930s to the 1950s and spatially replicated across each state in the United States, to glean insight into the drivers of polio’s historical expansion and the ecological mode of its persistence prior to vaccine introduction. We document a latitudinal gradient in polio’s seasonality. Additionally, we fitted and validated mechanistic transmission models to data from each US state independently. The fitted models revealed that: (1) polio persistence was the product of a dynamic mosaic of source and sink populations; (2) geographic heterogeneity of seasonal transmission conditions account for the latitudinal structure of polio epidemics; (3) contrary to the prevailing “disease of development” hypothesis, our analyses demonstrate that polio’s historical expansion was straightforwardly explained by demographic trends rather than improvements in sanitation and hygiene; and (4) the absence of clinical disease is not a reliable indicator of polio transmission, because widespread polio transmission was likely in the multiyear absence of clinical disease. As the world edges closer to global polio eradication and continues the strategic withdrawal of the Oral Polio Vaccine (OPV), the regular identification of, and rapid response to, these silent chains of transmission is of the utmost importance.