Safety profile of nOPV2 vaccine
Since March 2021, the novel oral poliomyelitis vaccine type 2 (nOPV2) has been used for outbreak response under WHO Emergency Use Listing (EUL). In December 2023, nOPV2 was prequalified by WHO. GACVS was presented with an overview of the roll-out of nOPV2 and a summary of the EUL experience. Since 2021, about 1.3 billion doses of nOPV2 have been administered in 41 countries during almost 250 outbreak response campaigns. Overall, the experience to date with widescale use of this vaccine in highest-risk areas has demonstrated its safety, effectiveness and stability. Data on the genetic stability of nOPV2 in the field show far fewer emergences of vaccine-derived poliovirus after nOPV2 administration than with the Sabin OPV2 vaccine, with a reduction of 75–80% in emergences than would be expected with similar usage of the Sabin OPV2. On 18 July 2024, the GACVS nOPV2 subcommittee met for the last time to review safety data from 10 March 2021 to 16 December 2023. A summary of the subcommittee’s conclusions and recommendations1 was presented to GACVS. The subcommittee concluded from data from 35 countries, representing over 1 billion administered doses of nOPV2, that there was no evidence of any clusters or patterns of adverse event reports, either temporally or geographically, that would give rise to any unexpected safety concerns. GACVS congratulated the subcommittee on its work and recommended continued strong surveillance and reporting of adverse events following immunization (AEFIs), including cVPDP2 emergencies. The Committee also recommended that findings from the safety monitoring of nOPV2 during the EUL period be reported to the Strategic Advisory Group of Experts on Immunization (SAGE). The Committee intends to continue to consider updates on the vaccine at future meetings.
Extract from the meeting of WHO GACVS, published in the WHO Weekly Epidemiological Record of 1st March 2024
Since March 2021, nOPV2 has been used for outbreak response under WHO Emergency Use Listing (EUL) approval. As of December 2023, approximately 1 billion doses of the vaccine have been administered across 35 countries. In December 2023, nOPV2 earned full licensure from Indonesian regulatory authority (Badan POM) as well as WHO Prequalification (PQ).
As part of the EUL requirements, nOPV2’s use under WHO Emergency Use Listing (EUL) is being closely monitored across three domains—genetic stability, effectiveness, and safety. As of June 2022, only 2% of all whole genome sequenced isolates have shown any public health consequences in the domain V area, the primary attenuation site of the vaccine virus. To date, there have been 10 circulating vaccine-derived poliovirus type 2 (cVDPV2) emergencies derived from nOPV2, in comparison, estimates show that if Sabin OPV had been used at this scale 66 emergences would have been seeded by this point. Despite over 850 million doses of nOPV2 having been administered since 2021, there has not been a massive rise in new outbreaks, and the significant spike seen in 2019 and 2020, has not recurred.
Recently updated safety data from 31 campaigns across 17 countries was presented in the fourth nOPV2 safety report to the GACVS nOPV2 subcommittee in its meeting held in July, 2023[1]. The report covered an additional period between 1 November 2022 to 31 May 2023, during which 1 518 adverse events following immunization (AEFIs) were reported, of which 425 were deemed as serious AEFIs after 160 634 815 doses administered. Among these, a total of 480 AEFIs were assessed by the national expert committees (NECs) and six cases (1.2%) were categorized A1. There were 61 adverse events of special interest (AESIs) reported from three countries during this period.
Cumulative data (13 March 2021 to 31 May 2023) as well as country-by-country breakdown of the safety data including the causality assessment summary were also presented. Out of the total 89 AEFIs classified as A1 so far, 24 were downgraded to non-serious by the respective NECs, and final diagnosis was not reported for 11 cases. Of the remaining 55 cases, 13 were cases of respiratory tract infection and nine were diagnosed as cases of Guillain-Barré Syndrome. In summary, 28 countries reported safety data, and the subcommittee concluded no evidence exists of geographic or temporal clustering, though expressed concern over the cVDPV2 case stemming from nOPV2, the same number of countries have functional acute flaccid paralysis (AFP) surveillance, and 25 of 28 countries have implemented and reported on AEFIs.
Regarding the questions on the transition of safety surveillance in the post qualification period, it was clarified that all monitoring of campaigns is to continue, conducted by Outbreak Response and Preparedness Group (ORPG) within Global Polio Eradication Initiative (GPEI); AFP surveillance will continue, as well, through existing networks. AEFI and causality assessment will continue through national agencies. However, due to lack of capacity, it is recommended that active AESI surveillance specific to nOPV2 will be recommended rather than required based on country capacity to implement, in line with previous GACVS guidance.
The committee suggested that when rollout does happen there should be some active surveillance conducted in countries with that capability. There may need to be a mapping exercise to determine what surveillance networks exist. Capacity building for some national regulatory authorities to conduct causality assessments may be required. Further, a report should be compiled of best practices and lessons learned.
Full report of WHO GACVS and WHO ACSoMP 13–15 November 2023, published on 1st March 2024
Extract from the meeting of WHO GACVS, published in the WHO Weekly Epidemiological Record of 11 August 2023
The novel oral polio vaccine (nOPV2) is currently in the wider use roll-out phase under WHO Emergency Use Listing (EUL) for the control of type 2 circulating vaccine-derived poliovirus (cVDPV2) outbreaks, in line with the Strategic Advisory Group of Experts on Immunization (SAGE) guidance. To date, approximately 600 million nOPV2 doses have been administered across 28 countries. With increased use of nOPV2 in the last 2 years, both new emergences of cVDPV2 and the intensity of cVDPV2 transmissions have trended down.
Approximately 70% of countries demonstrated no evidence of breakthrough transmission following 2 rounds of nOPV2 supplementary immunization activities (SIAs). This is similar to the demonstrated impact of the Sabin monovalent type 2 oral polio vaccine (mOPV2) in interrupting outbreaks.
Clinical trials and observational research studies have generated safety data from approximately 12 000 participants ranging from neonates to adults in 7 countries. Currently, available clinical trial data do not demonstrate any concerning safety signals.
The GACVS Subcommittee on nOPV2 continues to monitor and advise on the safety of this vaccine. In January 2023, the Subcommittee met to review recent safety developments, including cumulative safety data from approximately 3 700 000 nOPV2 doses administered in 21 countries from 13 March 2021 to 31 October 2022. The GACVS Subcommittee focused on the findings of National Causality Committee assessments undertaken to investigate adverse events following nOPV2 in 13 countries. Of the events classified as vaccine product-related reactions consistent with causal association to immunization, the most frequent reports included Guillain-Barré Syndrome (GBS) and acute flaccid paralysis (AFP) or vaccine associated paralytic poliomyelitis (VAPP). Notably, conservative crude reporting rate estimates for these and all other adverse events of special interest (AESI) reports indicate rates lower than expected background incidence.
The GACVS Subcommittee also reviewed the latest research data for nOPV2, including an observational study in Uganda and a phase 3 study in the Gambia. No safety concerns were found in either study.
Based on the available evidence highlighted above, the Subcommittee concluded that there was no geographical or temporal clustering of AESI reports that would indicate a safety concern, and no obvious red flags. Additionally, the Subcommittee noted several incorrect classifications requiring re-review by national causality committees and requested priority follow-up on causality assessments with missing clinical information. The Subcommittee also emphasized that high-quality monitoring and analysis must continue in both the areas of safety and genetic stability, as specifically for the latter, the risk of detecting concerning variants would increase over time.
Since the Subcommittee meeting in March 2023, a GACVS alert was issued in response to detections of 2 separate and distinct emergences of cVDPV2 linked to nOPV2, forming 2 clusters that both featured AFP cases. The first emergence had an onset in September 2022 in the South Kivu province of the Democratic Republic of the Congo (DRC), with detections in adjacent areas in Burundi. The second emergence had an onset in November 2022 in the Tanganyika province of the DRC. However, ongoing field-use monitoring by Global Polio Eradication Initiative (GPEI) partners shows increased genetic stability of nOPV2 compared with mOPV2 by whole genome sequencing, and preliminary modelling results show that a higher number of emergences would be expected following similar use of mOPV2 compared with nOPV2.
An additional safety investigation, for which the GACVS Subcommittee is providing ongoing advice, is being conducted by the Benin Ministry of Health. This investigation focuses on the causality assessments of serious AEFI reported from a nOPV2 campaign conducted 14–15 October 2022 in Benin. The investigation was triggered by 2 early cases of Quincke’s oedema (angioneurotic oedema involving the uvula) in preterm infant recipients of nOPV2. The national nOPV2 vaccination programme was temporarily suspended in response to the signal under investigation.
The full Advisory Committee was presented with the latest findings from this investigation, including conclusions from the Benin AEFI Causality Committee on cases reviewed to date. GACVS was reassured that of these cases, only 3 were determined to be category A (consistent with causal association to immunization): the 2 cases of Quincke’s oedema and another case where a child below eligible weight was given the vaccine. Samples of the identified batches were analyzed at a WHO contracted laboratory and were found to have no untoward contamination. The Ministry of Health of Benin is expected to give its report soon.
Extract from the second joint meeting of WHO GACVS and WHO ACSoMP, published in the WHO Weekly Epidemiological Record of 3 March 2023
nOPV2 is a novel oral poliomyelitis (polio) vaccine type 2 (nOPV2) that was developed to address the evolving risk of circulating vaccine-derived poliovirus type 2 (cVDPV2). A total of 525 million doses of nOPV2 have been administered in 25 countries since its first use in March 2021 up to early December 2022. Most doses have been used in Nigeria, especially in northern Nigeria. Genetic sequencing of nOPV2 samples collected during field use confirms that the vaccine has retained its enhanced genetic stability, compared with Sabin OPV2. To date, only one sample (three isolates from same sample) from Uganda out of a total of 600 has shown reversion at the primary attenuation sites (domain V and cre). Recent data from a clinical study assessing nOPV2 immunogenicity in naïve neonates in Bangladesh showed 46% seroconversion following the first dose given at birth (compared with 21% with the birth dose of Sabin OPV2) and 90% seroconversion following the second dose given at 4 weeks (compared with 90% with the second dose of Sabin OPV2). Data from field-use shows that about 70% of countries have no evidence of breakthrough transmission following two vaccination campaigns which is similar to what is seen with Sabin OPV2. However, effectiveness varies by setting, highlighting the importance of strong vaccination programmes, high quality campaigns, conducted rapidly, at an appropriate scale, to stop polio virus outbreaks. Not only has there been a promising decline in new cVDPV2 emergencies, since the peak in 2019, but importantly, no emergences have been linked with nOPV2, to date.
Results from clinical and observational studies, mainly in infants and young children, show that nOPV2 is well tolerated, without any notable differences in safety events between the studies. Field safety data from 13 March 2021 to 31 May 2022, covering 253 million doses administered in 13 countries were presented to the GACVS Subcommittee on 30 June 2022. There have been 213 cases of the AESIs reported across all countries and surveillance sources, although not all are casually related. There were six suspected cases of acute flaccid paralysis/vaccine associated paralytic poliomyelitis (AFP/VAPP), of which three are new reports and three were previously reported at the GACVS meeting in February 2022. Both cases are awaiting genetic sequencing of stool isolates. It was noted that out of the 3 previous VAPP cases reported from Nigeria, 2 cases had recovered with no paralysis at follow up examinations 140-180 days from onset, although they had met VAPP criteria as they had residual paralysis at 60 days. Based on the administration of 253 million doses, the AESI reporting rate per 100 000 doses administered was lower than background rates from published literature, and the rate of VAPP (0.002 per 100 000 children vaccinated) was lower than would be expected with the Sabin vaccine (0.025–0.4 per 100 000 doses).
After their review of these safety data, the GACVS nOPV2 Subcommittee concluded that there were no safety concerns detected. The Subcommittee expressed concerns about the incompleteness of AEFI and AESI data and emphasized that efforts to obtain complete clinical and laboratory data should be continued to enable a more complete assessment to be made. They also noted no concerning genetic mutations or reversions had been observed. The GACVS nOPV2 Subcommittee will meet again to review available data in January 2023.
Extract from the first joint meeting of WHO GACVS and WHO ACSoMP, published in the WHO Weekly Epidemiological Record of 26 August 2022
nOPV2 is a novel oral poliomyelitis (polio) vaccine type 2 (nOPV2) which was developed to address the evolving risk of circulating vaccine-derived poliovirus type 2 (cVDPV2). The development of nOPV2 started in 2011 with funding for the identification of candidate vaccines. It was the first vaccine to be authorized under Emergency Use Listing (EUL) in November 2020 in response to a Public Health Emergency of International Concern (PHEIC). Clinical trial data has confirmed the safety of nOPV2, and the non-inferior immunogenicity compared with monovalent oral polio vaccine type 2 (mOPV2).3, 4 nOPV2 is also comparable with mOPV2 in terms of viral faecal shedding parameters. nOPV2 has been shown to be more genetically stable than mOPV2. Four additional clinical trials on nOPV2 immunogenicity and 4 field studies on seroprevalence have recently been completed, or are ongoing or planned.
Field use of nOPV2 started shortly after the EUL in March 2021 and as of the week of 12 June 2022, over 360 million doses of nOPV2 have been administered in 21 countries to stop type 2 outbreaks and another 16 countries have indicated that they are ready to respond to vaccine derived poliovirus (VDPV) with nOPV2, if necessary. It is reassuring that no breakthrough cases have been reported in 14 of the 17 countries where nOPV2 has been used for type 2 VDPV outbreaks countries, after 2 campaigns. In Tajikistan, nOPV2 was used at the peak of transmission and after 2 big and one smaller nOPV2 campaigns, with no residual transmission reported. In contrast, in northern Nigeria local transmission continues despite several nOPV2 campaigns, which suggests that it is not only vaccines that are important to stop local transmission, but vaccination is also important. Overall, the observed effectiveness is consistent with that seen with mOPV2 and the safety profile is promising.
The GACVS nOPV2 sub-committee reviewed safety and genetic stability data on 21 February 2022. The genetic characterization of nOPV2 isolates detected in the field showed high genetic stability with most isolates showing no changes in the primary attenuation site, low recombination rates and few VP1 nucleotide changes relative to the mOPV2 vaccine.5 Only 6 adverse events of special interest (AESIs) were assessed as being consistent with a causal association with immunization, all in Nigeria, where 88 million doses were administered between March and October 2021. There were 3 cases of suspected vaccine-associated paralytic poliomyelitis (VAPP), and one each of anaphylaxis, allergic reaction and meningoencephalitis. The reporting rates for these events were all well below the expected range, so did not generate any new safety signals. The sub-committee concluded that, based on the available data, there was no evidence of any geographical or temporal clustering of AESI reports that would indicate a safety concern, and no obvious red flags or safety concerns to be notified to the WHO Strategic Advisory Group of Experts on Immunization (SAGE).
The sub-committee reemphasized that acute flaccid paralysis (AFP) surveillance should remain the backbone of safety surveillance as it captures diseases that are most likely to be related to events of interest and that AESI surveillance should be recommended but not mandatory in countries with limited resources. Instead, these countries should focus their resources on complete data collection for cases detected through AFP surveillance, information on 60-day follow-up when required, and genetic sequencing of stool samples.
3 Clinical summary for novel oral polio vaccine type 2 (nOPV2). Geneva: Global Polio Eradication Initiative; 2021.
4 nOPV2 Geneva: Global Polio Eradication Initiative; 2022 .
5 Famulare M, et al. Sabin vaccine reversion in the field: a comprehensive analysis of sabin-like poliovirus isolates in Nigeria. J Virol. 2015;90(1):317-331. doi:10.1128/JVI.01532-15.
Extract from GACVS meeting of 8-9 June 2021, published in the WHO Weekly Epidemiological Record of 23 July 2021
On 13 November 2020, type 2 novel oral polio vaccine (nOPV2) became the first vaccine to be authorized for use under the WHO Emergency Use Listing (EUL) mechanism. The use of nOPV2 is restricted to outbreak response for type 2 circulating vaccine-derived polioviruses (cVDPV2). SAGE recommended that an independent nOPV2 safety monitoring group be established (the GACVS subcommittee on nOPV2) and that the GACVS should advise on nOPV2 safety monitoring during the entire period of the EUL.
The nOPV2 implementation under the EUL is being rolled out in 2 phases:
Phase 1: Initial use – whereby countries are approved for nOPV2 use only after meeting stringent initial-use readiness verification requirements (including passive AEFI, active AESI, and routine/ongoing acute flaccid paralysis (AFP) surveillance and environmental surveillance);
Phase 2: Wider use – whereby nOPV2 becomes the standard vaccine of choice for cVDPV2 outbreak response.
GACVS members were updated on the status of the nOPV2 rollout and preliminary nOPV2 safety data were reviewed.
As of 9 June 2021, 32 countries were undergoing the readiness verification process for nOPV2 use and, of these 32, 7 had been approved. Up to this date, 18 752 409 doses of nOPV2 had been administered, primarily in Nigeria (17 899 130 doses) and Liberia (853 279 doses), and 5 711 268 children were targeted for vaccination in Benin, Democratic Republic of the Congo, Sierra Leone and Tajikistan in the completed first round. In parallel to safety monitoring, 2 formal studies are ongoing – immunogenicity study in naïve infants (Bangladesh) and Phase III trials (Gambia). Other planned activities include studies assessing vaccine effectiveness, immunogenicity, household transmission, seroprevalence, observational pregnancy studies and the establishment of primary immunodeficiency registries.
GACVS members commended the notable efforts made by Liberia and Nigeria to implement AESI surveillance and report AFP and AEFI data. The Advisory Committee cautioned that the programme needs to weigh the risks and benefits of the speed of rollout and the exponential increase in the number of doses administered in terms of the lag in availability of safety data to provide information/feedback in a timely manner. The GACVS observed that “wider use countries” should continue to meet routine AFP surveillance indicators and maintain capacity to detect and respond to safety events.
The GACVS stressed that analysis of the available, preliminary data did not indicate safety red flags, safety signals or clusters of concern. Nevertheless, GACVS members emphasized that the analysis was based on assessment in the context of very preliminary data with significant gaps remaining for follow-up and ongoing review. More comprehensive safety data, including on the quality of AFP surveillance and genetic analysis, are anticipated towards the end of July 2021 and will be presented to the GACVS subcommittee on nOPV2. n
Safety of inactivated poliovirus vaccines (IPV)
Extract from report of GACVS meeting of 11-12 December 2013, published in the WHO Weekly Epidemiological Record on 14 February 2014
With several countries on the threshold of adopting the use of IPV, in line with the Global Vaccine Action Plan (GVAP) strategy for polio eradication, the GACVS session on IPV focussed on visiting: i) the safety record of IPV, as determined in controlled clinical trials during development of the currently available stand-alone and IPV-containing combination vaccines; ii) Adverse events following immunization (AEFI) reports related to IPV from the Vaccine Adverse Events Reporting System (VAERS) of the USA; and iii) issues related to the manufacturing process for IPV.
The first polio vaccine was developed by Jonas Salk, from formaldehyde-inactivated wild polio viruses. Salk’s IPV was tested and proved highly efficacious against paralytic poliomyelitis in a large clinical trial conducted in US schoolchildren in 1954, which was rapidly followed by licensure of the product and implementation of mass vaccination campaigns in children in the USA, Canada and Western Europe. In less than a year, however, this first IPV was the centre of one the most serious vaccine safety events recorded, the Cutter incident, in which inadequate inactivation of the polio viruses during the manufacturing process resulted in 61 cases of vaccine-associated paralytic poliomyelitis (VAPP), 80 family contact cases, 17 community contact cases and 11 deaths. Following this incident, IPV manufacturing techniques were modified to ensure complete inactivation and avoid any potential risk of injecting live polio viruses. This also resulted in a reduction of the immunogenicity of IPV preparations. In the 1970s an enhanced-potency IPV, similar in immunogenicity to the original product, replaced the second generation IPV. Currently IPV is offered as an individual vaccine as well as in vaccine combinations for primary immunization and for boosters. The available data indicate that known adverse events following IPV administered alone are limited to non-serious reactions. Local reactions, as may occur with any inactivated vaccine, are most common. Adverse events due to IPV administered as a combination with other vaccines are difficult to differentiate from those induced by the other vaccines, e.g. diphtheria+ tetanus+ whole cell pertussis (DTwP). Reviews have not documented any serious adverse events causally related to IPV. Further, a dose of IPV administered prior to a course of oral poliovirus vaccine (OPV) reduces the risk of VAPP compared with an exclusively OPV series.
IPV was introduced in the childhood immunization schedule in the USA in 1997, replacing OPV. Currently, there are 4 licensed vaccines of which 1 is IPV stand-alone vaccine and 3 are in combination with other vaccines. An assessment of AEFI in all ages indicated that most adverse events in VAERS reported from 1 January 1999 to 31 December 2012 were non-serious. Less than 1% of reports were for IPV given alone. The vaccines most commonly co-administered with IPV are pneumococcal conjugate, Haemophilus influenzae type b (Hib), hepatitis B, diphtheria+ tetanus+ acellular pertussis (DTaP), and rotavirus vaccines. Although sudden infant death syndrome (SIDS) is the most commonly coded term for deaths in infants for all IPV-containing vaccines, the Institute of Medicine review (2003) rejected a causal relationship between SIDS and multiple vaccines.5 Based on available data, GACVS is reassured that IPV and IPV-containing vaccines have an excellent safety profile.
GACVS was also presented with an overview of the manufacturing process of IPV by a licensed vaccine manufacturer. The complexities of the manufacturing process were noted, in particular the methods used to ensure virus inactivation and containment to prevent accidental environmental contamination. WHO discussed plans for IPV vaccine technology transfer to emerging country vaccine manufacturers. GACVS noted, given the complexities of the IPV manufacturing process, the importance of ensuring appropriate technical support, training and regulatory oversight to IPV vaccine manufacturers.
5Stratton K et al. Immunization safety review: vaccinations and sudden unexpected death in infancy. Institute of Medicine (IOM), 2003.
Full report of GACVS meeting of 11-12 December 2013, published in the WHO Weekly Epidemiological Record on 14 February 2014