Boosting with adjuvanted SCB-2019 elicits superior Fcγ-receptor engagement driven by IgG3 to SARS-CoV-2 spike.

With the continued emergence of variants of concern, the global threat of COVID-19 persists, particularly in low- and middle-income countries with limited vaccine access. Protein-based vaccines, such as SCB-2019, can be produced on a large scale at a low cost while antigen design and adjuvant use can modulate efficacy and safety. While effective humoral immunity against SARS-CoV-2 variants has been shown to depend on both neutralization and Fc-mediated immunity, data on the effectiveness of protein-based vaccines with enhanced Fc-mediated immunity is limited. Here, we assess the humoral profile, including antibody isotypes, subclasses, and Fc receptor binding generated by a boosting with a recombinant trimer-tag protein vaccine SCB-2019. Individuals who were primed with 2 doses of the ChAdOx1 vaccine were equally divided into 4 groups and boosted with following formulations: Group 1: 9 µg SCB-2019 and Alhydrogel; Group 2: 9 µg SCB-2019, CpG 1018, and Alhydrogel; Group 3: 30 µg SCB-2019, CpG 1018, and Alhydrogel; Group 4: ChAdOx1. Group 3 showed enhanced antibody FcγR binding against wild-type and variants compared to Groups 1 and 2, showing a dose-dependent enhancement of immunity conferred by the SCB-2019 vaccine. Moreover, from day 15 after vaccination, Group 3 exhibited higher IgG3 and FcγR binding across variants of concerns, including Omicron and its subvariants, compared to the ChAdOx1-boosted individuals. Overall, this highlights the potential of SCB-2019 as a cost-efficient boosting regimen effective across variants of concerns.

Influenza Vaccination during Pregnancy: A Descriptive Study of the Knowledge, Beliefs, and Practices of Mexican Gynecologists and Family Physicians.

BACKGROUND: Influenza in pregnancy is associated with elevated morbidity and mortality. Influenza vaccines are safe and effective in pregnancy. There are no Mexican surveys of physicians on knowledge, beliefs, and practices towards influenza and influenza immunization during pregnancy. METHODS: A 32-question descriptive survey was conducted, addressing the general knowledge of influenza as well as beliefs and practices regarding influenza vaccination during pregnancy among Mexican physicians responsible for prenatal care, traditionally Obstetricians (OBGYNs) and Family Physicians (FPs). RESULTS: A total of 206 surveys were available, 98 (47.6%) from OBGYNs and 108 (52.4%) from FPs, representing an estimated 2472 daily pregnancy consultations. In total, 54 of the 206 respondents (26.2%) were not aware that influenza is more severe during pregnancy, 106 of the 206 respondents (51.5%) ignored the potential side effects of influenza infection on the fetus, and 56.8% did not know when to vaccinate pregnant women. Pregnancy as a risk factor for developing influenza complications was only known by 99 of the 206 respondents (48.1%), and 6.1% believed that vaccination does not confer protection to the fetus. CONCLUSIONS: The current beliefs of Mexican OBGYNs and FPs for both influenza morbidity and mortality, and the importance of influenza vaccination during pregnancy are suboptimal. The drivers of these beliefs should be assessed to improve influenza vaccination recommendations, as knowledge alone is not sufficient.

The role of a genetically stable, novel oral type 2 poliovirus vaccine in the poliomyelitis endgame.

Poliovirus infection causes paralysis in up to 1 in 200 infected persons. The use of safe and effective inactivated poliovirus vaccines and live attenuated oral poliovirus vaccines (OPVs) means that only two pockets of wild-type poliovirus type 1 remain, in Afghanistan and Pakistan. However, OPVs can revert to virulence, causing outbreaks of circulating vaccine-derived poliovirus (cVDPV). During 2020-2022, cVDPV type 2 (cVDPV2) was responsible for 97-99% of poliomyelitis cases, mainly in Africa. Between January and August 2022, cVDPV2 was detected in sewage samples in Israel, the United Kingdom and the United States of America, where a case of acute flaccid paralysis caused by cVDPV2 also occurred. The Pan American Health Organization has warned that Brazil, the Dominican Republic, Haiti and Peru are at very high risk for the reintroduction of poliovirus and an additional eight countries in Latin America are at high risk, following dropping vaccination rates (average 80% coverage in 2022). Sabin type 2 monovalent OPV has been used to control VDPV2 outbreaks, but its use could also lead to outbreaks. To address this issue, a more genetically stable, novel OPV2 (nOPV2) was developed against cVDPV2 and in 2020 was granted World Health Organization Emergency Use Listing. Rolling out a novel vaccine under the Emergency Use Listing in mass settings to contain outbreaks requires unique local regulatory and operational preparedness.

La infección por poliovirus ocasiona parálisis en hasta 1 de cada 200 personas infectadas. La utilización de vacunas con poliovirus inactivados y de vacunas antipoliomielíticas orales con poliovirus vivos atenuados (OPV) seguras y eficaces ha logrado que solo queden dos focos de poliovirus salvaje de tipo 1, en Afganistán y Pakistán. Sin embargo, las vacunas con OPV pueden revertir a la virulencia y producir brotes de poliovirus circulantes de origen vacunal (cVDPV). Durante el período 2020-2022, el cVDPV de tipo 2 (cVDPV2) fue la causa del 97-99% de los casos de poliomielitis, sobre todo en África. Entre enero y agosto del 2022, se encontró el cVDPV2 en muestras de aguas residuales en Estados Unidos de América, donde se produjo un caso de parálisis flácida aguda por el cVDPV2, Israel y Reino Unido y. La Organización Panamericana de la Salud ha advertido que, tras la caída de las tasas de vacunación (con una cobertura promedio del 80% en el 2022), Brasil, Haití, Perú y República Dominicana corren un riesgo muy alto de reintroducción del poliovirus, en tanto que otros ocho países de América Latina se encuentran en una situación de alto riesgo. La OPV monovalente de tipo 2 de Sabin se ha utilizado para controlar los brotes de VDPV2, pero su empleo también podría ocasionar brotes. Para hacer frente a este problema, se creó una nueva OPV2 (nOPV2) contra el cVDPV2, genéticamente más estable, que en el 2020 se incluyó en la lista de uso en emergencias de la Organización Mundial de la Salud. El despliegue a gran escala de una nueva vacuna incluida en la lista de uso en emergencias con el fin de contener los brotes exige una extraordinaria preparación regulatoria y operativa local.

A infecção pelo poliovírus causa paralisia em 1 de cada 200 pessoas infectadas. O uso de vacinas seguras e eficazes, tanto vacinas inativadas contra o poliovírus quanto vacinas orais contendo poliovírus atenuado (VOP), significa que restam apenas dois bolsões de poliovírus selvagem tipo 1, um no Afeganistão e outro no Paquistão. No entanto, a VOP pode reverter à virulência, causando surtos de poliovírus circulante derivado de vacina (cPVDV). No período 2020-2022, o cPVDV tipo 2 (cPVDV2) foi responsável por 97% a 99% dos casos de poliomielite, principalmente na África. Entre janeiro e agosto de 2022, o cPVDV2 foi detectado em amostras de esgoto em Israel, no Reino Unido e nos Estados Unidos da América, onde também houve um caso de paralisia flácida aguda causada pelo cPVDV2. A Organização Pan-Americana da Saúde alertou que, devido à queda nas taxas de vacinação (cobertura média de 80% em 2022), o Brasil, o Haiti, o Peru e a República Dominicana correm um risco muito alto de reintrodução do poliovírus e outros oito países da América Latina correm um risco alto. A VOP monovalente Sabin tipo 2 tem sido usada para controlar surtos de PVDV2, mas seu uso também pode levar a surtos. Para resolver esse problema, foi desenvolvida uma nova VOP2 (nVOP2), mais estável geneticamente, para combater o cPVDV2. Em 2020, a nVOP2 entrou na Lista de Uso Emergencial da Organização Mundial da Saúde. A distribuição de uma nova vacina incluída na Lista de Uso Emergencial em contextos de massa para conter surtos requer medidas originais de preparação operacional e regulatória em âmbito local.

Immunogenicity, safety and reactogenicity of heterologous (third dose) booster vaccination with a full or fractional dose of two different COVID-19 vaccines: A phase 4, single-blind, randomized controlled trial in adults.

In this phase 4 study we assessed boosting with fractional doses of heterologous COVID-19 vaccines in Brazilian adults primed with two doses of CoronaVac (Sinovac/Butantan, São Paulo, Brazil) at least 4 months previously. Participants received either full-dose of ChAdOx1-S (Group 1, n = 232), a half dose of ChAdOx1-S (Group 2, n = 236), or a half dose of BNT162b2 (Group 3, n = 234). The primary objective was to show 80% seroresponse rates (SRR) 28 d after vaccination measured as IgG antibodies against a prototype SARS-CoV-2 spike-protein. Safety was assessed as solicited and unsolicited adverse events. At baseline all participants were seropositive, with high IgG titers overall. SRR at Day 28 were 34.3%, 27.1% and 71.2%, respectively, not meeting the primary objective of 80%, despite robust immune responses in all three groups with geometric mean-fold rise (GMFR) in IgG titers of 3.39, 2.99 and 7.42, respectively. IgG immune responses with similar GMFR were also observed against SARS-CoV-2 variants, Alpha, Beta, Delta, Gamma and D614G. In subsets (n = 35) of participants GMFR of neutralizing immune responses against live prototype SARS-CoV-2 virus and Omicron BA.2 were similar to the IgG responses as were pseudo-neutralizing responses against SARS-CoV-2 prototype and Omicron BA.4/5 variants. All vaccinations were well tolerated with no vaccine-related serious adverse events and mainly transient mild-to-moderate local and systemic reactogenicity. Heterologous boosting with full or half doses of ChAdOx1-S or a half dose of BNT162b2 was safe and immunogenic in CoronaVac-primed adults, but seroresponse rates were limited by high baseline immunity.

Investigating the Possible Reasons for the Low Reported Morbidity and Mortality of COVID-19 in African Countries: An Integrative Review.

BACKGROUND: COVID-19 has impacted the world differentially with the highest mortality and morbidity rate burden in Europe and the USA and the lowest mortality and morbidity burden in Africa. This study aims to investigate the possible reasons why Africa recorded the lowest COVID-19 mortality and morbidity. METHODS: The following search terms were used PubMed database: ["mortalit*" (tw) OR "morbidit*" (tw) AND "COVID-19" (tw) AND "Africa" (tw)]. Studies that discuss a factor for the low COVID-19 burden in Africa have a defined methodology, discuss its research question and mention its limitations are selected for review. Data from the final articles were extracted using a data collection tool. RESULTS: Twenty-one studies were used in this integrative review. Results were grouped into 10 themes, which are younger African population, lower health capacity, weather, vaccines and drugs, effective pandemic response, lower population density and mobility, African socioeconomic status, lower prevalence of comorbidities, genetic difference and previous infection exposure. The low COVID-19 mortality and morbidity in Africa is largely a result of a combined effect of the younger African population and underreporting of COVID-19 cases. CONCLUSIONS: There is a need to strengthen the health capacities of African countries. Moreover, African countries that have other health problem priorities may use a tailored approach to vaccinating the elderly. More definitive studies are needed to know the role of BCG vaccination, weather, genetic makeup and prior infection exposure in the differential impact of the COVID-19 pandemic.

The role of a genetically stable, novel oral type 2 poliovirus vaccine in the poliomyelitis endgame / Utilidad de una nueva vacuna antipoliomielítica oral del serotipo 2 genéticamente estable contra el poliovirus de tipo 2 en la erradicación de la poliomielitis / O papel de uma nova vacina oral contra o poliovírus tipo 2, geneticamente estável, no estágio final da eliminação da poliomielite

ABSTRACT Poliovirus infection causes paralysis in up to 1 in 200 infected persons. The use of safe and effective inactivated poliovirus vaccines and live attenuated oral poliovirus vaccines (OPVs) means that only two pockets of wild-type poliovirus type 1 remain, in Afghanistan and Pakistan. However, OPVs can revert to virulence, causing outbreaks of circulating vaccine-derived poliovirus (cVDPV). During 2020-2022, cVDPV type 2 (cVDPV2) was responsible for 97-99% of poliomyelitis cases, mainly in Africa. Between January and August 2022, cVDPV2 was detected in sewage samples in Israel, the United Kingdom and the United States of America, where a case of acute flaccid paralysis caused by cVDPV2 also occurred. The Pan American Health Organization has warned that Brazil, the Dominican Republic, Haiti and Peru are at very high risk for the reintroduction of poliovirus and an additional eight countries in Latin America are at high risk, following dropping vaccination rates (average 80% coverage in 2022). Sabin type 2 monovalent OPV has been used to control VDPV2 outbreaks, but its use could also lead to outbreaks. To address this issue, a more genetically stable, novel OPV2 (nOPV2) was developed against cVDPV2 and in 2020 was granted World Health Organization Emergency Use Listing. Rolling out a novel vaccine under the Emergency Use Listing in mass settings to contain outbreaks requires unique local regulatory and operational preparedness.

RESUMEN La infección por poliovirus ocasiona parálisis en hasta 1 de cada 200 personas infectadas. La utilización de vacunas con poliovirus inactivados y de vacunas antipoliomielíticas orales con poliovirus vivos atenuados (OPV) seguras y eficaces ha logrado que solo queden dos focos de poliovirus salvaje de tipo 1, en Afganistán y Pakistán. Sin embargo, las vacunas con OPV pueden revertir a la virulencia y producir brotes de poliovirus circulantes de origen vacunal (cVDPV). Durante el período 2020-2022, el cVDPV de tipo 2 (cVDPV2) fue la causa del 97-99% de los casos de poliomielitis, sobre todo en África. Entre enero y agosto del 2022, se encontró el cVDPV2 en muestras de aguas residuales en Estados Unidos de América, donde se produjo un caso de parálisis flácida aguda por el cVDPV2, Israel y Reino Unido y. La Organización Panamericana de la Salud ha advertido que, tras la caída de las tasas de vacunación (con una cobertura promedio del 80% en el 2022), Brasil, Haití, Perú y República Dominicana corren un riesgo muy alto de reintroducción del poliovirus, en tanto que otros ocho países de América Latina se encuentran en una situación de alto riesgo. La OPV monovalente de tipo 2 de Sabin se ha utilizado para controlar los brotes de VDPV2, pero su empleo también podría ocasionar brotes. Para hacer frente a este problema, se creó una nueva OPV2 (nOPV2) contra el cVDPV2, genéticamente más estable, que en el 2020 se incluyó en la lista de uso en emergencias de la Organización Mundial de la Salud. El despliegue a gran escala de una nueva vacuna incluida en la lista de uso en emergencias con el fin de contener los brotes exige una extraordinaria preparación regulatoria y operativa local.

RESUMO A infecção pelo poliovírus causa paralisia em 1 de cada 200 pessoas infectadas. O uso de vacinas seguras e eficazes, tanto vacinas inativadas contra o poliovírus quanto vacinas orais contendo poliovírus atenuado (VOP), significa que restam apenas dois bolsões de poliovírus selvagem tipo 1, um no Afeganistão e outro no Paquistão. No entanto, a VOP pode reverter à virulência, causando surtos de poliovírus circulante derivado de vacina (cPVDV). No período 2020-2022, o cPVDV tipo 2 (cPVDV2) foi responsável por 97% a 99% dos casos de poliomielite, principalmente na África. Entre janeiro e agosto de 2022, o cPVDV2 foi detectado em amostras de esgoto em Israel, no Reino Unido e nos Estados Unidos da América, onde também houve um caso de paralisia flácida aguda causada pelo cPVDV2. A Organização Pan-Americana da Saúde alertou que, devido à queda nas taxas de vacinação (cobertura média de 80% em 2022), o Brasil, o Haiti, o Peru e a República Dominicana correm um risco muito alto de reintrodução do poliovírus e outros oito países da América Latina correm um risco alto. A VOP monovalente Sabin tipo 2 tem sido usada para controlar surtos de PVDV2, mas seu uso também pode levar a surtos. Para resolver esse problema, foi desenvolvida uma nova VOP2 (nVOP2), mais estável geneticamente, para combater o cPVDV2. Em 2020, a nVOP2 entrou na Lista de Uso Emergencial da Organização Mundial da Saúde. A distribuição de uma nova vacina incluída na Lista de Uso Emergencial em contextos de massa para conter surtos requer medidas originais de preparação operacional e regulatória em âmbito local.

Effectiveness of the Fiocruz recombinant ChadOx1-nCoV19 against variants of SARS-CoV-2 in the Municipality of Botucatu-SP.

Introduction: As the COVID-19 pandemic progresses, rapidly emerging variants of concern raise fears that currently licensed vaccines may have reduced effectiveness against these new strains. In the municipality of Botucatu, São Paulo State, Brazil, a mass vaccination campaign using ChadOx1-nCoV19 was initiated on 16th of May 2021, targeting people 18-60 years old. Two vaccine doses were offered 12 weeks apart, with the second delivered on 8th of August, 2021. This setting offered a unique opportunity to assess the effectiveness of two ChadOx1-nCoV19 doses in a real-life setting. Materials and methods: Data on testing, hospitalization, symptoms, demographics, and vaccination were obtained from the Hospital das Clínicas da Faculdade de Medicina de Botucatu. A test-negative study design was employed; whereby the odds of being vaccinated among cases vs controls were calculated to estimate vaccine effectiveness (VE; 1-OR). All individuals aged 18-60 who received a PCR test after the 16th of May and were unvaccinated prior to this date were included in the analysis until the study ended in mid-November 2021. Results: 77,683 citizens of Botucatu aged 18-60 received the first dose, and 74,051 received a second ChadOx1-nCoV19 dose 12 weeks later for a vaccination coverage of 84.2 and 80.2%, respectively. Of 7.958 eligible PCR tests, 2.109 were positive and 5.849 negative. The VE against any symptomatic infection was estimated at 39.2%, 21 days after dose 1, and 74.5%, 14 days after dose 2. There were no COVID-19-related hospitalizations or deaths among the 74,051 fully vaccinated individuals. The VE against severe disease was estimated at 70.8 and 100% after doses 1 and 2, respectively. 90.5% of all lineages sequenced between doses 1 and 2 (16th of May-7th of August) were of the Gamma variant, while 83.0% were of the Delta variant during the second period after dose 2 (8th of August-18th of November). Discussion: This observational study found the effectiveness of ChadOx1-nCoV19 to be 74.5% against COVID-19 disease of any severity, comparable to the efficacy observed in clinical trials (81.3% after dose 2), despite the dominance of the Gamma and Delta VoCs. No COVID-19-related hospitalizations or deaths in fully vaccinated individuals were reported.

Homologous and Heterologous Boosting of the Chadox1-S1-S COVID-19 Vaccine With the SCB-2019 Vaccine Candidate: A Randomized, Controlled, Phase 2 Study.

Background: Ongoing outbreaks of coronavirus disease 2019 (COVID-19) are driven by waning immunity following primary immunizations and emergence of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that escape vaccine-induced neutralizing antibodies. It has been suggested that heterologous boosters could enhance and potentially maintain population immunity. Methods: We assessed the immunogenicity and reactogenicity of booster doses of different formulations of aluminium hydroxide-adjuvanted SCB-2019 vaccine (9 µg of SCB-2019, with or without CpG-1018 adjuvant, or 30 µg of SCB-2019 with CpG-1018) in Brazilian adults primed with ChAdOx1-S vector vaccine. S-protein antibodies and ACE2-binding inhibition were measured by enzyme-linked immunosorbent assay (ELISA) on days 1, 15, and 29. Participants self-reported solicited adverse events and reactions. Results: All SCB-2019 formulations increased S-protein ELISA antibodies and ACE2 binding inhibition to a greater extent than ChAdOx1-S. After 30 µg of SCB-2019 + CpG + aluminium hydroxide, titers against wild-type S-protein were significantly higher than after ChAdOx1-S on days 15 and 29, as were titers of neutralizing antibodies against the wild-type strain and Beta, Gamma, Delta, and Omicron variants. Boosting with SCB-2019 or ChAdOx1-S was well tolerated, with no vaccine-related serious or severe adverse events. Conclusions: Boosting ChAdOx1-S-primed adults with SCB-2019 induced higher levels of antibodies against a wild-type strain and SARS-CoV-2 variants than a homologous ChAdOx1-S booster, with the highest responses being with the 30-µg SCB-2019 + CpG + aluminium hydroxide formulation. Clinical Trials Registration: NCT05087368.

An exploratory analysis of the response to ChAdOx1 nCoV-19 (AZD1222) vaccine in males and females.

BACKGROUND: There are known differences in vaccine reactogenicity and immunogenicity by sex. Females have been shown to report greater reactogenicity and generate higher humoral and cellular immune responses than males following vaccination with several different vaccines. Whether this is also the case for COVID-19 vaccines is currently unknown, as COVID-19 vaccine study data disaggregated by sex are not routinely reported. Therefore, we have assessed the influence of sex on reactogenicity, immunogenicity and efficacy of COVID-19 vaccine ChAdOx1 nCoV-19. METHODS: Vaccine efficacy was assessed in 15169 volunteers enrolled into single-blind randomised controlled trials of ChAdOx1 nCoV-19 in Brazil and the UK, with the primary endpoint defined as nucleic acid amplification test (NAAT)-positive symptomatic SARS-CoV-2 infection. All participants were electronically randomised to receive two standard doses of vaccine or the control product. Logistic regression models were fitted to explore the effect of age and sex on reactogenicity, and linear models fitted to log-transformed values for immunogenicity data. Reactogenicity data were taken from self-reported diaries of 788 trial participants. Pseudovirus neutralisation assay data were available from 748 participants and anti-SARS-CoV-2 spike IgG assay data from 1543 participants. FINDINGS: 7619 participants received ChAdOx1 nCoV-19 and 7550 received the control. Vaccine efficacy in participants after two doses of ChAdOx1 nCoV-19 (4243 females and 3376 males) was 66.1% (95% CI 55.9-73.9%) in males and 59.9% (95% CI 49.8-67.9%) in females; with no evidence of a difference in efficacy between the sexes (vaccine by sex interaction term P=0.3359). A small, statistically significant difference in anti-spike IgG was observed (adjusted GMR 1.14; 95% CI 1.04-1.26), with higher titres in females than males, but there were no statistically significant differences in other immunological endpoints. Whilst the majority of individuals reported at least one systemic reaction following a first dose of ChAdOx1 nCoV-19, females were twice as likely as males to report any systemic reaction after a first dose (OR 1.95; 95% CI 1.37-2.77). Measured fever of 38°C or above was reported in 5% of females and 1% of males following first doses. Headache and fatigue were the most commonly reported reactions in both sexes. INTERPRETATION: Our results show that there is no evidence of difference in efficacy of the COVID-19 vaccine ChAdOx1 nCoV-19 in males and females. Greater reactogenicity in females was not associated with any difference in vaccine efficacy. FUNDING: Studies were registered with ISRCTN 90906759 (COV002) and ISRCTN 89951424 (COV003) and follow-up is ongoing. Funding was received from the UK Research and Innovation, Engineering and Physical Sciences Research Council, National Institute for Health Research, Coalition for Epidemic Preparedness Innovations, National Institute for Health Research Oxford Biomedical Research Centre, Chinese Academy of Medical Sciences Innovation Fund for Medical Science, Thames Valley and South Midlands NIHR Clinical Research Network, the Lemann Foundation, Rede D'Or, the Brava and Telles Foundation, the Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior, Brazil, and AstraZeneca.

Highly Sensitive Lineage Discrimination of SARS-CoV-2 Variants through Allele-Specific Probe PCR.

Tools to detect SARS-CoV-2 variants of concern and track the ongoing evolution of the virus are necessary to support public health efforts and the design and evaluation of novel COVID-19 therapeutics and vaccines. Although next-generation sequencing (NGS) has been adopted as the gold standard method for discriminating SARS-CoV-2 lineages, alternative methods may be required when processing samples with low viral loads or low RNA quality. To this aim, an allele-specific probe PCR (ASP-PCR) targeting lineage-specific single nucleotide polymorphisms (SNPs) was developed and used to screen 1,082 samples from two clinical trials in the United Kingdom and Brazil. Probit regression models were developed to compare ASP-PCR performance against 1,771 NGS results for the same cohorts. Individual SNPs were shown to readily identify specific variants of concern. ASP-PCR was shown to discriminate SARS-CoV-2 lineages with a higher likelihood than NGS over a wide range of viral loads. The comparative advantage for ASP-PCR over NGS was most pronounced in samples with cycle threshold (CT) values between 26 and 30 and in samples that showed evidence of degradation. Results for samples screened by ASP-PCR and NGS showed 99% concordant results. ASP-PCR is well suited to augment but not replace NGS. The method can differentiate SARS-CoV-2 lineages with high accuracy and would be best deployed to screen samples with lower viral loads or that may suffer from degradation. Future work should investigate further destabilization from primer-target base mismatch through altered oligonucleotide chemistry or chemical additives.

SARS-CoV-2 Omicron-B.1.1.529 leads to widespread escape from neutralizing antibody responses.

On 24th November 2021, the sequence of a new SARS-CoV-2 viral isolate Omicron-B.1.1.529 was announced, containing far more mutations in Spike (S) than previously reported variants. Neutralization titers of Omicron by sera from vaccinees and convalescent subjects infected with early pandemic Alpha, Beta, Gamma, or Delta are substantially reduced, or the sera failed to neutralize. Titers against Omicron are boosted by third vaccine doses and are high in both vaccinated individuals and those infected by Delta. Mutations in Omicron knock out or substantially reduce neutralization by most of the large panel of potent monoclonal antibodies and antibodies under commercial development. Omicron S has structural changes from earlier viruses and uses mutations that confer tight binding to ACE2 to unleash evolution driven by immune escape. This leads to a large number of mutations in the ACE2 binding site and rebalances receptor affinity to that of earlier pandemic viruses.

Heterologous versus homologous COVID-19 booster vaccination in previous recipients of two doses of CoronaVac COVID-19 vaccine in Brazil (RHH-001): a phase 4, non-inferiority, single blind, randomised study.

INTRODUCTION: The inactivated whole-virion SARS-CoV-2 vaccine (CoronaVac, Sinovac) has been widely used in a two-dose schedule. We assessed whether a third dose of the homologous or a different vaccine could boost immune responses. METHODS: RHH-001 is a phase 4, participant masked, two centre, safety and immunogenicity study of Brazilian adults (18 years and older) in São Paulo or Salvador who had received two doses of CoronaVac 6 months previously. The third heterologous dose was of either a recombinant adenoviral vectored vaccine (Ad26.COV2-S, Janssen), an mRNA vaccine (BNT162b2, Pfizer-BioNTech), or a recombinant adenoviral-vectored ChAdOx1 nCoV-19 vaccine (AZD1222, AstraZeneca), compared with a third homologous dose of CoronaVac. Participants were randomly assigned (5:6:5:5) by a RedCAP computer randomisation system stratified by site, age group (18-60 years or 61 years and over), and day of randomisation, with a block size of 42. The primary outcome was non-inferiority of anti-spike IgG antibodies 28 days after the booster dose in the heterologous boost groups compared with homologous regimen, using a non-inferiority margin for the geometric mean ratio (heterologous vs homologous) of 0·67. Secondary outcomes included neutralising antibody titres at day 28, local and systemic reactogenicity profiles, adverse events, and serious adverse events. This study was registered with Registro Brasileiro de Ensaios Clínicos, number RBR-9nn3scw. FINDINGS: Between Aug 16, and Sept 1, 2021, 1240 participants were randomly assigned to one of the four groups, of whom 1239 were vaccinated and 1205 were eligible for inclusion in the primary analysis. Antibody concentrations were low before administration of a booster dose with detectable neutralising antibodies of 20·4% (95% CI 12·8-30·1) in adults aged 18-60 years and 8·9% (4·2-16·2) in adults 61 years or older. From baseline to day 28 after the booster vaccine, all groups had a substantial rise in IgG antibody concentrations: the geometric fold-rise was 77 (95% CI 67-88) for Ad26.COV2-S, 152 (134-173) for BNT162b2, 90 (77-104) for ChAdOx1 nCoV-19, and 12 (11-14) for CoronaVac. All heterologous regimens had anti-spike IgG responses at day 28 that were superior to homologous booster responses: geometric mean ratios (heterologous vs homologous) were 6·7 (95% CI 5·8-7·7) for Ad26.COV2-S, 13·4 (11·6-15·3) for BNT162b2, and 7·0 (6·1-8·1) for ChAdOx1 nCoV-19. All heterologous boost regimens induced high concentrations of pseudovirus neutralising antibodies. At day 28, all groups except for the homologous boost in the older adults reached 100% seropositivity: geometric mean ratios (heterologous vs homologous) were 8·7 (95% CI 5·9-12·9) for Ad26.COV2-S vaccine, 21·5 (14·5-31·9) for BNT162b2, and 10·6 (7·2-15·6) for ChAdOx1 nCoV-19. Live virus neutralising antibodies were also boosted against delta (B.1.617.2) and omicron variants (B.1.1.529). There were five serious adverse events. Three of which were considered possibly related to the vaccine received: one in the BNT162b2 group and two in the Ad26.COV2-S group. All participants recovered and were discharged home. INTERPRETATION: Antibody concentrations were low at 6 months after previous immunisation with two doses of CoronaVac. However, all four vaccines administered as a third dose induced a significant increase in binding and neutralising antibodies, which could improve protection against infection. Heterologous boosting resulted in more robust immune responses than homologous boosting and might enhance protection. FUNDING: Ministry of Health, Brazil.

Fecal Shedding of 2 Novel Live Attenuated Oral Poliovirus Type 2 Vaccine Candidates by Healthy Infants Administered Bivalent Oral Poliovirus Vaccine/Inactivated Poliovirus Vaccine: 2 Randomized Clinical Trials.

BACKGROUND: Primary intestinal immunity through viral replication of live oral vaccine is key to interrupt poliovirus transmission. We assessed viral fecal shedding from infants administered Sabin monovalent poliovirus type 2 vaccine (mOPV2) or low and high doses of 2 novel OPV2 (nOPV2) vaccine candidates. METHODS: In 2 randomized clinical trials in Panama, a control mOPV2 study (October 2015 to April 2016) and nOPV2 study (September 2018 to October 2019), 18-week-old infants vaccinated with bivalent oral poliovirus vaccine/inactivated poliovirus vaccine received 1 or 2 study vaccinations 28 days apart. Stools were assessed for poliovirus RNA by polymerase chain reaction (PCR) and live virus by culture for 28 days postvaccination. RESULTS: Shedding data were available from 621 initially reverse-transcription PCR-negative infants (91 mOPV2, 265 nOPV2-c1, 265 nOPV2-c2 recipients). Seven days after dose 1, 64.3% of mOPV2 recipients and 31.3%-48.5% of nOPV2 recipients across groups shed infectious type 2 virus. Respective rates 7 days after dose 2 decreased to 33.3% and 12.9%-22.7%, showing induction of intestinal immunity. Shedding of both nOPV2 candidates ceased at similar or faster rates than mOPV2. CONCLUSIONS: Viral shedding of either nOPV candidate was similar or decreased relative to mOPV2, and all vaccines showed indications that the vaccine virus was replicating sufficiently to induce primary intestinal mucosal immunity.

Human Papillomavirus Vaccination and Premature Ovarian Failure: A Disproportionality Analysis Using the Vaccine Adverse Event Reporting System.

INTRODUCTION: There have been public health concerns about a potential association between human papillomavirus (HPV) vaccines and premature ovarian failure (POF) in young women. OBJECTIVE: To identify a potential safety signal of POF after HPV vaccination using the United States (US) Vaccine Adverse Event Reporting System (VAERS) database. METHODS: We manually selected relevant MedDRA preferred terms related to POF and identified in VAERS all POF reports in women less than 40 years of age between 2 July 1990 and 14 May 2018, followed by a review of narratives to confirm the cases. We conducted descriptive analyses on age, POF type, HPV vaccine type (HPV2, HPV4, HPV9), time to onset of POF, and dose rank. We described trends in reporting over time and assessed a potential safety signal using the proportional reporting ratio (PRR). RESULTS: Of the 228,341 eligible POF reports, 281 (0.1%) were suspected to be associated with HPV vaccines. Median patient age was 15 years (range 11-39 years). POF events consisted mainly of amenorrhea (80.4%) and premature menopause (15.3%). Mean number of reported POF events significantly increased after the first HPV vaccine launch in 2006 with 22.2 POF cases/year up from 1.4 POF cases/year before the launch. PRR was 46.1 (95% confidence interval: 31.7-67.2) and sensitivity analyses yielded similar estimates. CONCLUSION: Our study suggests the presence of a potential safety signal of POF associated with HPV vaccination, which may only be partly attributed to notoriety bias. Due to the well-known limitations of spontaneous reporting data, further investigations are warranted.

Economic Evaluation of Universal Varicella Vaccination in Mexico.

BACKGROUND: Universal varicella vaccination has proven to be cost-effective (CE) in countries where implemented. However, this has not been evaluated for Mexico. METHODS: The yearly disease burden (varicella cases/deaths, outpatient visits, and hospitalizations) was derived from Mexican seroprevalence data adjusted to the 2020 population. The yearly economic burden was calculated by combining disease with Mexican unit cost data from both health care and societal perspectives. Four different vaccination strategies were evaluated: (1) 1 dose of varicella vaccine at 1 year old; (2) 2 doses at 1 and 6 years; (3) 1 dose of varicella vaccine at 1 year, and quadrivalent measles-mumps-rubella-varicella vaccine at 6 years; (4) 2 doses of measles-mumps-rubella-varicella vaccine at 1 and 6 years. We developed an economic model for each vaccination strategy where 20 consecutive birth cohorts were simulated. Vaccination impact (number of avoided cases/deaths) was evaluated for a 20-year follow-up period based on vaccine effectiveness (87% and 97.4% for 1 and 2 doses), and assuming a 95% coverage. We estimated annual costs saved, incremental cost-effectiveness ratio, and costs per life year gained. RESULTS: Avoided cases during the 20-year follow-up with 1, and 2 doses were 20,570,722 and 23,029,751, respectively. Strategies 1 and 2 were found to be cost saving, and strategy 3 to be CE. Strategy 4 was not CE. Strategies 1 and 2 would allow saving annually $53.16 and $34.41 million USD, respectively, to the Mexican society. CONCLUSIONS: Universal varicella vaccination, using 1 dose or 2 doses, would result in a cost-beneficial and CE public health intervention in Mexico.

Reduced neutralization of SARS-CoV-2 B.1.617 by vaccine and convalescent serum.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has undergone progressive change, with variants conferring advantage rapidly becoming dominant lineages, e.g., B.1.617. With apparent increased transmissibility, variant B.1.617.2 has contributed to the current wave of infection ravaging the Indian subcontinent and has been designated a variant of concern in the United Kingdom. Here we study the ability of monoclonal antibodies and convalescent and vaccine sera to neutralize B.1.617.1 and B.1.617.2, complement this with structural analyses of Fab/receptor binding domain (RBD) complexes, and map the antigenic space of current variants. Neutralization of both viruses is reduced compared with ancestral Wuhan-related strains, but there is no evidence of widespread antibody escape as seen with B.1.351. However, B.1.351 and P.1 sera showed markedly more reduction in neutralization of B.1.617.2, suggesting that individuals infected previously by these variants may be more susceptible to reinfection by B.1.617.2. This observation provides important new insights for immunization policy with future variant vaccines in non-immune populations.

Antibody evasion by the P.1 strain of SARS-CoV-2.

Terminating the SARS-CoV-2 pandemic relies upon pan-global vaccination. Current vaccines elicit neutralizing antibody responses to the virus spike derived from early isolates. However, new strains have emerged with multiple mutations, including P.1 from Brazil, B.1.351 from South Africa, and B.1.1.7 from the UK (12, 10, and 9 changes in the spike, respectively). All have mutations in the ACE2 binding site, with P.1 and B.1.351 having a virtually identical triplet (E484K, K417N/T, and N501Y), which we show confer similar increased affinity for ACE2. We show that, surprisingly, P.1 is significantly less resistant to naturally acquired or vaccine-induced antibody responses than B.1.351, suggesting that changes outside the receptor-binding domain (RBD) impact neutralization. Monoclonal antibody (mAb) 222 neutralizes all three variants despite interacting with two of the ACE2-binding site mutations. We explain this through structural analysis and use the 222 light chain to largely restore neutralization potency to a major class of public antibodies.

Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials.

BACKGROUND: The ChAdOx1 nCoV-19 (AZD1222) vaccine has been approved for emergency use by the UK regulatory authority, Medicines and Healthcare products Regulatory Agency, with a regimen of two standard doses given with an interval of 4-12 weeks. The planned roll-out in the UK will involve vaccinating people in high-risk categories with their first dose immediately, and delivering the second dose 12 weeks later. Here, we provide both a further prespecified pooled analysis of trials of ChAdOx1 nCoV-19 and exploratory analyses of the impact on immunogenicity and efficacy of extending the interval between priming and booster doses. In addition, we show the immunogenicity and protection afforded by the first dose, before a booster dose has been offered. METHODS: We present data from three single-blind randomised controlled trials-one phase 1/2 study in the UK (COV001), one phase 2/3 study in the UK (COV002), and a phase 3 study in Brazil (COV003)-and one double-blind phase 1/2 study in South Africa (COV005). As previously described, individuals 18 years and older were randomly assigned 1:1 to receive two standard doses of ChAdOx1 nCoV-19 (5 × 1010 viral particles) or a control vaccine or saline placebo. In the UK trial, a subset of participants received a lower dose (2·2 × 1010 viral particles) of the ChAdOx1 nCoV-19 for the first dose. The primary outcome was virologically confirmed symptomatic COVID-19 disease, defined as a nucleic acid amplification test (NAAT)-positive swab combined with at least one qualifying symptom (fever ≥37·8°C, cough, shortness of breath, or anosmia or ageusia) more than 14 days after the second dose. Secondary efficacy analyses included cases occuring at least 22 days after the first dose. Antibody responses measured by immunoassay and by pseudovirus neutralisation were exploratory outcomes. All cases of COVID-19 with a NAAT-positive swab were adjudicated for inclusion in the analysis by a masked independent endpoint review committee. The primary analysis included all participants who were SARS-CoV-2 N protein seronegative at baseline, had had at least 14 days of follow-up after the second dose, and had no evidence of previous SARS-CoV-2 infection from NAAT swabs. Safety was assessed in all participants who received at least one dose. The four trials are registered at ISRCTN89951424 (COV003) and ClinicalTrials.gov, NCT04324606 (COV001), NCT04400838 (COV002), and NCT04444674 (COV005). FINDINGS: Between April 23 and Dec 6, 2020, 24 422 participants were recruited and vaccinated across the four studies, of whom 17 178 were included in the primary analysis (8597 receiving ChAdOx1 nCoV-19 and 8581 receiving control vaccine). The data cutoff for these analyses was Dec 7, 2020. 332 NAAT-positive infections met the primary endpoint of symptomatic infection more than 14 days after the second dose. Overall vaccine efficacy more than 14 days after the second dose was 66·7% (95% CI 57·4-74·0), with 84 (1·0%) cases in the 8597 participants in the ChAdOx1 nCoV-19 group and 248 (2·9%) in the 8581 participants in the control group. There were no hospital admissions for COVID-19 in the ChAdOx1 nCoV-19 group after the initial 21-day exclusion period, and 15 in the control group. 108 (0·9%) of 12 282 participants in the ChAdOx1 nCoV-19 group and 127 (1·1%) of 11 962 participants in the control group had serious adverse events. There were seven deaths considered unrelated to vaccination (two in the ChAdOx1 nCov-19 group and five in the control group), including one COVID-19-related death in one participant in the control group. Exploratory analyses showed that vaccine efficacy after a single standard dose of vaccine from day 22 to day 90 after vaccination was 76·0% (59·3-85·9). Our modelling analysis indicated that protection did not wane during this initial 3-month period. Similarly, antibody levels were maintained during this period with minimal waning by day 90 (geometric mean ratio [GMR] 0·66 [95% CI 0·59-0·74]). In the participants who received two standard doses, after the second dose, efficacy was higher in those with a longer prime-boost interval (vaccine efficacy 81·3% [95% CI 60·3-91·2] at ≥12 weeks) than in those with a short interval (vaccine efficacy 55·1% [33·0-69·9] at <6 weeks). These observations are supported by immunogenicity data that showed binding antibody responses more than two-fold higher after an interval of 12 or more weeks compared with an interval of less than 6 weeks in those who were aged 18-55 years (GMR 2·32 [2·01-2·68]). INTERPRETATION: The results of this primary analysis of two doses of ChAdOx1 nCoV-19 were consistent with those seen in the interim analysis of the trials and confirm that the vaccine is efficacious, with results varying by dose interval in exploratory analyses. A 3-month dose interval might have advantages over a programme with a short dose interval for roll-out of a pandemic vaccine to protect the largest number of individuals in the population as early as possible when supplies are scarce, while also improving protection after receiving a second dose. FUNDING: UK Research and Innovation, National Institutes of Health Research (NIHR), The Coalition for Epidemic Preparedness Innovations, the Bill & Melinda Gates Foundation, the Lemann Foundation, Rede D'Or, the Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.

Safety and immunogenicity of inactivated poliovirus vaccine schedules for the post-eradication era: a randomised open-label, multicentre, phase 3, non-inferiority trial.

BACKGROUND: Following the global eradication of wild poliovirus, countries using live attenuated oral poliovirus vaccines will transition to exclusive use of inactivated poliovirus vaccine (IPV) or fractional doses of IPV (f-IPV; a f-IPV dose is one-fifth of a normal IPV dose), but IPV supply and cost constraints will necessitate dose-sparing strategies. We compared immunisation schedules of f-IPV and IPV to inform the choice of optimal post-eradication schedule. METHODS: This randomised open-label, multicentre, phase 3, non-inferiority trial was done at two centres in Panama and one in the Dominican Republic. Eligible participants were healthy 6-week-old infants with no signs of febrile illness or known allergy to vaccine components. Infants were randomly assigned (1:1:1:1, 1:1:1:2, 2:1:1:1), using computer-generated blocks of four or five until the groups were full, to one of four groups and received: two doses of intradermal f-IPV (administered at 14 and 36 weeks; two f-IPV group); or three doses of intradermal f-IPV (administered at 10, 14, and 36 weeks; three f-IPV group); or two doses of intramuscular IPV (administered at 14 and 36 weeks; two IPV group); or three doses of intramuscular IPV (administered at 10, 14, and 36 weeks; three IPV group). The primary outcome was seroconversion rates based on neutralising antibodies for poliovirus type 1 and type 2 at baseline and at 40 weeks (4 weeks after the second or third vaccinations) in the per-protocol population to allow non-inferiority and eventually superiority comparisons between vaccines and regimens. Three co-primary outcomes concerning poliovirus types 1 and 2 were to determine if seroconversion rates at 40 weeks of age after a two-dose regimen (administered at weeks 14 and 36) of intradermally administered f-IPV were non-inferior to a corresponding two-dose regimen of intramuscular IPV; if seroconversion rates at 40 weeks of age after a two-dose IPV regimen (weeks 14 and 36) were non-inferior to those after a three-dose IPV regimen (weeks 10, 14, and 36); and if seroconversion rates after a two-dose f-IPV regimen (weeks 14 and 36) were non-inferior to those after a three-dose f-IPV regimen (weeks 10, 14, and 36). The non-inferiority boundary was set at -10% for the lower bound of the two-sided 95% CI for the seroconversion rate difference.. Safety was assessed as serious adverse events and important medical events. This study is registered on ClinicalTrials.gov, NCT03239496. FINDINGS: From Oct 23, 2017, to Nov 13, 2018, we enrolled 773 infants (372 [48%] girls) in Panama and the Dominican Republic (two f-IPV group n=217, three f-IPV group n=178, two IPV group n=178, and three IPV group n=200). 686 infants received all scheduled vaccine doses and were included in the per-protocol analysis. We observed non-inferiority for poliovirus type 1 seroconversion rate at 40 weeks for the two f-IPV dose schedule (95·9% [95% CI 92·0-98·2]) versus the two IPV dose schedule (98·7% [95·4-99·8]), and for the three f-IPV dose schedule (98·8% [95·6-99·8]) versus the three IPV dose schedule (100% [97·9-100]). Similarly, poliovirus type 2 seroconversion rate at 40 weeks for the two f-IPV dose schedule (97·9% [94·8-99·4]) versus the two IPV dose schedule (99·4% [96·4-100]), and for the three f-IPV dose schedule (100% [97·7-100]) versus the three IPV dose schedule (100% [97·9-100]) were non-inferior. Seroconversion rate for the two f-IPV regimen was statistically superior 4 weeks after the last vaccine dose in the 14 and 36 week schedule (95·9% [92·0-98·2]) compared with the 10 and 14 week schedule (83·2% [76·5-88·6]; p=0·0062) for poliovirus type 1. Statistical superiority of the 14 and 36 week schedule was also found for poliovirus type 2 (14 and 36 week schedule 97·9% [94·8-99·4] vs 10 and 14 week schedule 83·9% [77·2-89·2]; p=0·0062), and poliovirus type 3 (14 and 36 week schedule 84·5% [78·7-89·3] vs 10 and 14 week schedule 73·3% [65·8-79·9]; p=0·0062). For IPV, a two dose regimen administered at 14 and 36 weeks (99·4% [96·4-100]) was superior a 10 and 14 week schedule (88·9% [83·4-93·1]; p<0·0001) for poliovirus type 2, but not for type 1 (14 and 36 week schedule 98·7% [95·4-99·8] vs 10 and 14 week schedule 95·6% [91·4-98·1]), or type 3 (14 and 36 week schedule 97·4% [93·5-99·3] vs 10 and 14 week schedule 93·9% [89·3-96·9]). There were no related serious adverse events or important medical events reported in any group showing safety was unaffected by administration route or schedule. INTERPRETATION: Our observations suggest that adequate immunity against poliovirus type 1 and type 2 is provided by two doses of either IPV or f-IPV at 14 and 36 weeks of age, and broad immunity is provided with three doses of f-IPV, enabling substantial savings in cost and supply. These novel clinical data will inform global polio immunisation policy for the post-eradication era. FUNDING: Bill & Melinda Gates Foundation.

Safety and immunogenicity of two novel type 2 oral poliovirus vaccine candidates compared with a monovalent type 2 oral poliovirus vaccine in children and infants: two clinical trials.

BACKGROUND: Continued emergence and spread of circulating vaccine-derived type 2 polioviruses and vaccine-associated paralytic poliomyelitis from Sabin oral poliovirus vaccines (OPVs) has stimulated development of two novel type 2 OPV candidates (OPV2-c1 and OPV2-c2) designed to have similar immunogenicity, improved genetic stability, and less potential to reacquire neurovirulence. We aimed to assess safety and immunogenicity of the two novel OPV candidates compared with a monovalent Sabin OPV in children and infants. METHODS: We did two single-centre, multi-site, partly-masked, randomised trials in healthy cohorts of children (aged 1-4 years) and infants (aged 18-22 weeks) in Panama: a control phase 4 study with monovalent Sabin OPV2 before global cessation of monovalent OPV2 use, and a phase 2 study with low and high doses of two novel OPV2 candidates. All participants received one OPV2 vaccination and subsets received two doses 28 days apart. Parents reported solicited and unsolicited adverse events. Type 2 poliovirus neutralising antibodies were measured at days 0, 7, 28, and 56, and stool viral shedding was assessed up to 28 days post-vaccination. Primary objectives were to assess safety in all participants and non-inferiority of novel OPV2 day 28 seroprotection versus monovalent OPV2 in infants (non-inferiority margin 10%). These studies were registered with ClinicalTrials.gov, NCT02521974 and NCT03554798. FINDINGS: The control study took place between Oct 23, 2015, and April 29, 2016, and the subsequent phase 2 study between Sept 19, 2018, and Sept 30, 2019. 150 children (50 in the control study and 100 of 129 assessed for eligibility in the novel OPV2 study) and 684 infants (110 of 114 assessed for eligibility in the control study and 574 of 684 assessed for eligibility in the novel OPV2 study) were enrolled and received at least one study vaccination. Vaccinations were safe and well tolerated with no causally associated serious adverse events or important medical events in any group. Solicited and unsolicited adverse events were overwhelmingly mild or moderate irrespective of vaccine or dose. Nearly all children were seroprotected at baseline, indicating high baseline immunity. In children, the seroprotection rate 28 days after one dose was 100% for monovalent OPV2 and both novel OPV2 candidates. In infants at day 28, 91 (94% [95% CI 87-98]) of 97 were seroprotected after receiving monovalent OPV2, 134 (94% [88-97]) of 143 after high-dose novel OPV2-c1, 122 (93% [87-97]) of 131 after low-dose novel OPV2-c1, 138 (95% [90-98]) of 146 after high-dose novel OPV2-c2, and 115 (91% [84-95]) of 127 after low-dose novel OPV2-c2. Non-inferiority was shown for low-dose and high-dose novel OPV2-c1 and high-dose novel OPV2-c2 despite monovalent OPV2 recipients having higher baseline immunity. INTERPRETATION: Both novel OPV2 candidates were safe, well tolerated, and immunogenic in children and infants. Novel OPV2 could be an important addition to our resources against poliovirus given the current epidemiological situation. FUNDING: Fighting Infectious Diseases in Emerging Countries and Bill & Melinda Gates Foundation.