In addition to the infected individual’s risk of paralytic disease, iVDPV excretion represents a potential reservoir of transmissible and neurovirulent poliovirus in the post-eradication era that could act as a source of poliovirus reintroduction into the community. Whilst the WHO maintains a registry of known iVDPV cases7,8 (mostly identified through acute flaccid paralysis (AFP) surveillance), the prevalence of asymptomatic iVDPV excretors globally remains uncertain. Many countries lack PID registries or surveillance programmes in this clinically vulnerable group. In screening studies of non-paralysed PID patients, both Sabin-like PVs and iVDPVs have been detected, though detection rates have varied from country-to-country9,10,11,12,13,14. Health systems increasingly support the complex care of PID patients resulting in improved survival. Higher risk countries for the emergence of iVDPVs are likely to be those with greater prevalence of PID patients, for example as a result of higher rates of consanguineous marriage, and where OPV continues to be used. Given that ~150 countries across the world continue to include OPV in their childhood vaccination programmes, exposure of PID patients to vaccine virus and subsequent prolonged excretion remains a possibility. Importation of iVDPVs into countries that have switched to IPV use (such as the UK) occurs, as was the scenario in both children reported here, who were exposed to OPV (either directly or indirectly) in countries that routinely use OPV in childhood vaccination programmes.
Although onward transmission of iVDPVs has only very rarely been documented to date, such as in reports from the USA and Spain15,16, the risk and impact of outbreaks seeded from iVDPV shedders could increase following a reduction of population immunity. The COVID-19 pandemic has caused disruptions in polio vaccination and surveillance activities globally17 and an upsurge in cVDPVs has been observed in recent years18. Given the overlap in the genetic characteristics of iVDPVs and cVDPVs19, onward transmission iVDPVs remains of concern. iVDPV excretion could act as a source for cryptic transmission in undervaccinated populations, to which even countries certified polio free must remain vigilant. More work is needed to delineate the molecular basis of poliovirus transmissibility in order to understand the relative transmissibility of iVDPVs compared to cVDPVs and wild type PVs. Whilst we did not detect transmission from these two cases, this is very unlikely in a well immunised country.
Until the widespread deployment globally of novel live polio vaccines that are genetically more stable20, sensitive surveillance for VDPVs is of importance globally. Existing poliovirus surveillance systems (primarily based around AFP cases) are not well designed to identify non-paralysed iVDPV-infected patients who may shed iVDPV asymptomatically for prolonged durations. Environmental (wastewater) PV surveillance is employed for monitoring of cVDPVs but does not easily allow for identification of individual excreting iVDPV cases. In the UK, wastewater sampling was only undertaken in a limited capacity in two regions in 2019 and neither of the children were living in catchment areas for this surveillance programme. The programme has since been expanded following the detection of cVDPV in London in 202221. To strengthen detection of iVDPVs, stool surveillance targeted at high-risk PID patients22, particularly migrants from countries using OPV or known to have circulating VDPVs, could be implemented, and is a key objective of the GPEI Global Polio Surveillance Action Plan 2022–202423. Indeed, the two iVDPV cases we report here were identified indirectly, the first serendipitously, through the existing UK national enhanced EV surveillance scheme without clinical suspicion for poliovirus, and the second through a targeted stool testing that occurred because, following the first case, the same clinicians had heightened awareness of the high-risk nature of the case. A key issue for routine EV surveillance in the UK has been the shift toward molecular diagnosis, particularly for using CSF, rather than acquiring stool samples to diagnose EV infections. For poliovirus, stool culture is the most sensitive detection method, which must be performed at CL3, and so detections of PV via EV surveillance are dependent upon the referral of adequate stool samples to a reference laboratory where PV isolation can be attempted.
Whilst iVDPV excretion has been reported previously, very few studies have performed monitoring and sequential sampling with genotypic and phenotypic characterisation of infecting strains. In both cases reported here, viral evolution toward neurovirulence in transgenic mice compared to the parental Sabin strain was observed, though fortunately did not manifest clinically. Nonetheless, PID patients are reported to be at ~3000 fold increased risk of VAPP24. Therefore, upon detection of an iVDPV case there is a need to risk assess the individual, facilitate early viral clearance and minimise the risk of neurological symptoms. Risk assessment will include the degree of immunosuppression, the nature of virus serotype (1/2/3 or recombinant), degree of divergence from parental Sabin strain, the rate of viral evolution, the viral load, and any evidence of systemic distribution of virus for example to the URT. Here, Child 2 had a higher viral load than Child 1 and was infected with a PV3/PV1/PV3 recombinant virus displaying greater divergence from the Sabin strain and shedding from the respiratory tract also. Moreover, the child was chronically co-infected with coxsackie A4 and other pathogens, which may suggest a greater level of immunosuppression than Child 1. Of note, recombination between viral genomes is a well-known phenomenon for enteroviruses, including intertypic recombinants between different OPV strains but also recombination with certain non-polio EVs, including other coxsackie A viruses25. Recombination is mostly detected in Sabin2- and Sabin 3-derived isolates and rarely in Sabin 1, though sequences of Sabin 1 origin can frequently be found as PV2/PV1 and PV3/PV1 recombinant strains.
Options for the clinical management of iVDPVs are derived from case report and expert opinion, and may include administering IVIg with uptitration of the dose to achieve a higher target trough level (e.g. >10–15 g/dL), use of HSCT where appropriate, or consideration of experimental antiviral therapy. In both cases reported here, all these options were considered. In Child 1, with CD40 ligand deficiency, PV clearance was temporally correlated with an increased dose of IVIg and corresponding increase in immunoglobulin trough levels. The child later proceeded to HSCT as planned for the underlying immunodeficiency, In the second case, with combined T and B cell deficiency, increased IVIg was administered, but clearance was only later achieved shortly after HSCT. This is in line with other case reports of cessation of PV shedding after HSCT26. In both of the cases we report here, it was felt to be important to observe for the possibility of accelerated evolution toward neurovirulence occurring during severe immunosuppression in the peri-transplant period. For PID patients who do not clear virus, novel therapeutics can be considered27. At present pocapavir is the only antiviral available under compassionate use, though a combination therapy of pocapavir and V-704 is in development28.
To conclude, declining polio vaccination rates across several countries has led to an upsurge in detection of vaccine-derived polioviruses globally1. In the UK, the two iVDPVs detections reported here, alongside recent genetically-linked VDPV wastewater detections in the UK, Israel and the USA2,3,4,5, together highlight the importance of robust virological surveillance, even in countries no longer using OPV, where pockets of reduced population immunity can lead to emergence and spread of VDPVs. The highly anticipated roll out and evaluation of novel live polio vaccine strains that are more genetically stable (starting with the nOPV2, with nOPV1,3 still in development) is a matter of urgency for public health.
