Prior flavivirus immunity skews the yellow fever vaccine response to cross-reactive antibodies with potential to enhance dengue virus infection.

The yellow fever 17D vaccine (YF17D) is highly effective but is frequently administered to individuals with pre-existing cross-reactive immunity, potentially impacting their immune responses. Here, we investigate the impact of pre-existing flavivirus immunity induced by the tick-borne encephalitis virus (TBEV) vaccine on the response to YF17D vaccination in 250 individuals up to 28 days post-vaccination (pv) and 22 individuals sampled one-year pv. Our findings indicate that previous TBEV vaccination does not affect the early IgM-driven neutralizing response to YF17D. However, pre-vaccination sera enhance YF17D virus infection in vitro via antibody-dependent enhancement (ADE). Following YF17D vaccination, TBEV-pre-vaccinated individuals develop high amounts of cross-reactive IgG antibodies with poor neutralizing capacity. In contrast, TBEV-unvaccinated individuals elicit a non-cross-reacting neutralizing response. Using YF17D envelope protein mutants displaying different epitopes, we identify quaternary dimeric epitopes as the primary target of neutralizing antibodies. Additionally, TBEV-pre-vaccination skews the IgG response towards the pan-flavivirus fusion loop epitope (FLE), capable of mediating ADE of dengue and Zika virus infections in vitro. Together, we propose that YF17D vaccination conceals the FLE in individuals without prior flavivirus exposure but favors a cross-reactive IgG response in TBEV-pre-vaccinated recipients directed to the FLE with potential to enhance dengue virus infection.

Safety and immunogenicity of a purified inactivated Zika virus vaccine candidate in adults primed with a Japanese encephalitis virus or yellow fever virus vaccine in the USA: a phase 1, randomised, double-blind, placebo-controlled clinical trial.

BACKGROUND: Zika virus infection is a threat to at-risk populations, causing major birth defects and serious neurological complications. Development of a safe and efficacious Zika virus vaccine is, therefore, a global health priority. Assessment of heterologous flavivirus vaccination is important given co-circulation of Japanese encephalitis virus and yellow fever virus with Zika virus. We investigated the effect of priming flavivirus naive participants with a licensed flavivirus vaccine on the safety and immunogenicity of a purified inactivated Zika vaccine (ZPIV). METHODS: This phase 1, placebo-controlled, double-blind trial was done at the Walter Reed Army Institute of Research Clinical Trials Center in Silver Spring, MD, USA. Eligible participants were healthy adults aged 18-49 years, with no detectable evidence of previous flavivirus exposure (by infection or vaccination), as measured by a microneutralisation assay. Individuals with serological evidence of HIV, hepatitis B, or hepatitis C infection were excluded, as were pregnant or breastfeeding women. Participants were recruited sequentially into one of three groups (1:1:1) to receive no primer, two doses of intramuscular Japanese encephalitis virus vaccine (IXIARO), or a single dose of subcutaneous yellow fever virus vaccine (YF-VAX). Within each group, participants were randomly assigned (4:1) to receive intramuscular ZPIV or placebo. Priming vaccinations were given 72-96 days before ZPIV. ZPIV was administered either two or three times, at days 0, 28, and 196-234. The primary outcome was occurrence of solicited systemic and local adverse events along with serious adverse events and adverse events of special interest. These data were analysed in all participants receiving at least one dose of ZPIV or placebo. Secondary outcomes included measurement of neutralizing antibody responses following ZPIV vaccination in all volunteers with available post-vaccination data. This trial is registered at ClinicalTrials.gov, NCT02963909. FINDINGS: Between Nov 7, 2016, and Oct 30, 2018, 134 participants were assessed for eligibility. 21 did not meet inclusion criteria, 29 met exclusion criteria, and ten declined to participate. 75 participants were recruited and randomly assigned. 35 (47%) of 75 participants were male and 40 (53%) were female. 25 (33%) of 75 participants identified as Black or African American and 42 (56%) identified as White. These proportions and other baseline characteristics were similar between groups. There were no statistically significant differences in age, gender, race, or BMI between those who did and did not opt into the third dose. All participants received the planned priming IXIARO and YF-VAX vaccinations, but one participant who received YF-VAX dropped out before receipt of the first dose of ZPIV. 50 participants received a third dose of ZPIV or placebo, including 14 flavivirus-naive people, 17 people primed with Japanese encephalitis virus vaccine, and 19 participants primed with yellow fever vaccine. Vaccinations were well tolerated across groups. Pain at the injection site was the only adverse event reported more frequently in participants who received ZPIV than in those who received placebo (39 [65%] of 60 participants, 95% CI 51·6-76·9 who received ZPIV vs three [21·4%] of 14 who received placebo; 4·7-50·8; p=0·006). No patients had an adverse event of special interest or serious adverse event related to study treatment. At day 57, the flavivirus-naive volunteers had an 88% (63·6-98·5, 15 of 17) seroconversion rate (neutralising antibody titre ≥1:10) and geometric mean neutralising antibody titre (GMT) against Zika virus of 100·8 (39·7-255·7). In the Japanese encephalitis vaccine-primed group, the day 57 seroconversion rate was 31·6% (95% CI 12·6-56·6, six of 19) and GMT was 11·8 (6·1-22·8). Participants primed with YF-VAX had a seroconversion rate of 25% (95% CI 8·7-49·1, five of 20) and GMT of 6·6 (5·2-8·4). Humoral immune responses rose substantially following a third dose of ZPIV, with seroconversion rates of 100% (69·2-100; ten of ten), 92·9% (66·1-99·8; 13 of 14), and 60% (32·2-83·7, nine of 15) and GMTs of 511·5 (177·6-1473·6), 174·2 (51·6-587·6), and 79 (19·0-326·8) in the flavivirus naive, Japanese encephalitis vaccine-primed, and yellow fever vaccine-primed groups, respectively. INTERPRETATION: We found ZPIV to be well tolerated in flavivirus naive and primed adults but that immunogenicity varied significantly according to antecedent flavivirus vaccination status. Immune bias towards the flavivirus antigen of initial exposure and the timing of vaccination may have impacted responses. A third ZPIV dose overcame much, but not all, of the discrepancy in immunogenicity. The results of this phase 1 clinical trial have implications for further evaluation of ZPIV's immunisation schedule and use of concomitant vaccinations. FUNDING: Department of Defense, Defense Health Agency; National Institute of Allergy and Infectious Diseases; and Division of Microbiology and Infectious Disease.

Informing COVID-19 Response and Health Equity Agenda: Collection of Public Health Reports Articles on Emerging Viral Epidemics in the United States, 1878-2021.

OBJECTIVE: Public Health Reports (PHR) is the oldest public health journal in the United States and has reported on viral epidemics since the 19th century. We describe the creation and analysis of a collection of historic PHR articles on emerging viral epidemics in the United States to inform public health response to COVID-19 and future epidemics. METHODS: We searched databases from 1878 through 2021 using custom search strings and conducted a manual search for articles published under previously used names for PHR. We evaluated all articles based on inclusion/exclusion criteria and coded the final list for virus/disease, article type, public health emergency preparedness and response capabilities from the Centers for Disease Control and Prevention (CDC), and PubMed citation count. RESULTS: We identified 349 relevant articles including 130 commentaries/reviews/editorials, 79 epidemiologic reports, 75 research articles, and 65 case study/practice articles. The collection focused on influenza (n = 244), COVID-19 (n = 75), dengue (n = 14), and other emerging viruses, such as Zika and Ebola (n = 25). The collection included 48 articles on health disparities/health of various disadvantaged populations, highlighting such disparities as race and ethnicity (n = 22), socioeconomic status (n = 17), and age (n = 15). When we categorized articles by CDC public health emergency preparedness and response capabilities, we found that 207 addressed surveillance and epidemiologic investigation, 36 addressed community preparedness, and 28 addressed medical countermeasure dispensing and administration. The articles addressing surveillance and epidemiologic investigation, nonpharmaceutical interventions, and community preparedness had the most PubMed citations (799, 334, and 308, respectively). CONCLUSIONS: PHR's historic articles on US emerging viral epidemics covered a range of virus/disease types, emergency preparedness and response capabilities, and contribution types and were widely cited in the scholarly literature. This publicly available and continuously updated collection is a valuable resource for pandemic planning and response.

The safety and immunogenicity of two Zika virus mRNA vaccine candidates in healthy flavivirus baseline seropositive and seronegative adults: the results of two randomised, placebo-controlled, dose-ranging, phase 1 clinical trials.

BACKGROUND: Developing a safe and immunogenic vaccine against Zika virus remains an unmet medical need. We did two phase 1 studies that evaluated the safety and immunogenicity of two mRNA-based Zika virus vaccines (mRNA-1325 and mRNA-1893) in adults. METHODS: Two randomised, placebo-controlled, dose-ranging, multicentre, phase 1 trials, one of mRNA-1325 (mRNA-1325 trial) and one of mRNA-1893 (mRNA-1893 trial), were done. For both studies, eligible participants were healthy adults (aged 18-49 years) who were flavivirus seronegative or flavivirus seropositive at baseline. Participants in the mRNA-1325 trial, which was done at three centres in the USA, were randomly assigned centrally (1:4), using a randomisation table, to the placebo group or one of three mRNA-1325 dose groups (10, 25, or 100 µg). All participants received two doses. The mRNA-1325 vaccine encoded the premembrane and envelope E structural proteins (prME) from a Micronesia 2007 Zika virus isolate. Participants in the mRNA-1893 trial, which was done at three centres in the USA and one centre in Puerto Rico, were randomly assigned (1:4) to the placebo group or one of four mRNA-1893 dose groups (10, 30, 100, or 250 µg) using centralised interactive response technology. All participants in the mRNA-1893 trial received dose one on day 1 and then dose two on day 29. The mRNA-1893 vaccine encoded the prME from the RIO-U1 Zika virus isolate. Safety was the primary outcome of each study, which was evaluated in the respective safety populations (mRNA-1325 trial: participants who received at least one dose and provided safety data; mRNA-1893 trial: participants who received at least one dose) and the solicited safety population (mRNA-1893 trial only: received at least 1 dose and contributed solicited adverse reaction data). Endpoints in both trials included solicited adverse reactions within 7 days after vaccination and unsolicited adverse events within 28 days after vaccination. The secondary outcome of both trials was immunogenicity assessed by Zika virus-specific neutralising antibodies (nAbs) in the per-protocol populations in either trial (participants with no major protocol deviations received full dose[s] of assigned dose level within the acceptable time window, had samples drawn within acceptable time window, and had prevaccination and corresponding post-vaccination serum samples for testing). These were descriptive studies, with no formal hypothesis testing in either trial. Both trials are registered with ClinicalTrials.gov, NCT03014089 (mRNA-1325 trial) and NCT04064905 (mRNA-1893 trial). FINDINGS: The mRNA-1325 trial was done from Dec 14, 2016, to Aug 16, 2018. 90 participants were enrolled: 53 (59%) participants were women and 37 (41%) were men; 84 (93%) were White; and 74 (82%) were not Hispanic or Latino. All three dose levels of mRNA-1325 (10, 25, and 100 µg) were generally well tolerated, but the vaccine elicited poor Zika virus-specific nAb responses. At 28 days after dose two, geometric mean titres (GMTs) were highest for mRNA-1325 10 µg (10·3 [95% CI 5·9-18·2]). The mRNA-1893 trial was done from July 23, 2019, to March 22, 2021. 120 participants (70 [58%] women and 50 [42%] men) were enrolled, most participants were White (89 [74%]), and not Hispanic or Latino (91 [76%]). In the mRNA-1893 trial, solicited adverse reactions in participants who received a vaccine were mostly grade 1 or 2 and occurred more frequently at higher dose levels and after dose two. No participants withdrew due to an unsolicited treatment-emergent adverse event and most of these events were not treatment related. On day 57, all evaluated mRNA-1893 dose levels induced robust Zika virus-specific nAb responses, independent of flavivirus serostatus, that persisted until month 13. At day 57 in participants who were flavivirus seronegative, plaque reduction neutralisation titre test nAb GMTs were highest for mRNA-1893 100 µg (454·2 [330·0-619·6]); in participants who were flavivirus seropositive, GMTs were highest for mRNA-1893 10 µg (224·1 [43·5-1153·5]) and mRNA-1893 100 µg (190·5 [19·2-1887·2]). INTERPRETATION: These findings support the continued development of mRNA-1893 against Zika virus, which was well tolerated at all evaluated dose levels and induced strong Zika virus-specific serum nAb responses after two doses, regardless of baseline flavivirus serostatus. FUNDING: Biomedical Advanced Research and Development Authority and Moderna.

Prevalence of microcephaly and Zika virus infection in a pregnancy cohort in Kenya, 2017-2019.

BACKGROUND: Zika virus (ZIKV), first discovered in Uganda in 1947, re-emerged globally in 2013 and was later associated with microcephaly and other birth defects. We determined the incidence of ZIKV infection and its association with adverse pregnancy and fetal outcomes in a pregnancy cohort in Kenya. METHODS: From October 2017 to July 2019, we recruited and followed up women aged ≥ 15 years and ≤ 28 weeks pregnant in three hospitals in coastal Mombasa. Monthly follow-up included risk factor questions and a blood sample collected for ZIKV serology. We collected anthropometric measures (including head circumference), cord blood, venous blood from newborns, and any evidence of birth defects. Microcephaly was defined as a head circumference (HC) < 2 standard deviations (SD) for sex and gestational age. Severe microcephaly was defined as HC < 3 SD for sex and age. We tested sera for anti-ZIKV IgM antibodies using capture enzyme-linked immunosorbent assay (ELISA) and confirmed positives using the plaque reduction neutralization test (PRNT90) for ZIKV and for dengue (DENV) on the samples that were ZIKV neutralizing antibody positive. We collected blood and urine from participants reporting fever or rash for ZIKV testing. RESULTS: Of 2889 pregnant women screened for eligibility, 2312 (80%) were enrolled. Of 1916 recorded deliveries, 1816 (94.6%) were live births and 100 (5.2%) were either stillbirths or spontaneous abortions (< 22 weeks of gestation). Among 1236 newborns with complete anthropometric measures, 11 (0.9%) had microcephaly and 3 (0.2%) had severe microcephaly. A total of 166 (7.2%) participants were positive for anti-ZIKV IgM, 136 of whom became seropositive during follow-up. Among the 166 anti-ZIKV IgM positive, 3 and 18 participants were further seropositive for ZIKV and DENV neutralizing antibodies, respectively. Of these 3 and 18 pregnant women, one and 13 (72.2%) seroconverted with antibodies to ZIKV and DENV, respectively. All 308 samples (serum and urine samples collected during sick visits and samples that were anti-ZIKV IgM positive) tested by RT-PCR were negative for ZIKV. No adverse pregnancy or neonatal outcomes were reported among the three participants with confirmed ZIKV exposure. Among newborns from pregnant women with DENV exposure, four (22.2%) were small for gestational age and one (5.6%) had microcephaly. CONCLUSIONS: The prevalence of severe microcephaly among newborns in coastal Kenya was high relative to published estimates from facility-based studies in Europe and Latin America, but little evidence of ZIKV transmission. There is a need for improved surveillance for microcephaly and other congenital malformations in Kenya.

A systematic review and meta-analysis on the prevalence of stigma in infectious diseases, including COVID-19: a call to action.

Infectious diseases, including COVID-19, are crucial public health issues and may lead to considerable fear among the general public and stigmatization of, and discrimination against, specific populations. This meta-analysis aimed to estimate the pooled prevalence of stigma in infectious disease epidemics. We systematically searched PubMed, PsycINFO, Embase, MEDLINE, Web of Science, and Cochrane databases since inception to June 08, 2021, and reported the prevalence of stigma towards people with infectious diseases including SARS, H1N1, MERS, Zika, Ebola, and COVID-19. A total of 50 eligible articles were included that contributed 51 estimates of prevalence in 92722 participants. The overall pooled prevalence of stigma across all populations was 34% [95% CI: 28-40%], including enacted stigma (36% [95% CI: 28-44%]) and perceived stigma (31% [95% CI: 22-40%]). The prevalence of stigma in patients, community population, and health care workers, was 38% [95% CI: 12- 65%], 36% [95% CI: 28-45%], and 30% [95% CI: 20-40%], respectively. The prevalence of stigma in participants from low- and middle-income countries was 37% [95% CI: 29-45%], which is higher than that from high-income countries (27% [95% CI: 18-36%]) though this difference was not statistically significant. A similar trend of prevalence of stigma was also observed in individuals with lower education (47% [95% CI: 23-71%]) compared to higher education level (33% [95% CI: 23-4%]). These findings indicate that stigma is a significant public health concern, and effective and comprehensive interventions are needed to counteract the damaging effects of the infodemics during infectious disease epidemics, including COVID-19, and reduce infectious disease-related stigma.

Development and Comparison of Dengue Vulnerability Indices Using GIS-Based Multi-Criteria Decision Analysis in Lao PDR and Thailand.

Dengue is a continuous health burden in Laos and Thailand. We assessed and mapped dengue vulnerability in selected provinces of Laos and Thailand using multi-criteria decision approaches. An ecohealth framework was used to develop dengue vulnerability indices (DVIs) that explain links between population, social and physical environments, and health to identify exposure, susceptibility, and adaptive capacity indicators. Three DVIs were constructed using two objective approaches, Shannon's Entropy (SE) and the Water-Associated Disease Index (WADI), and one subjective approach, the Best-Worst Method (BWM). Each DVI was validated by correlating the index score with dengue incidence for each spatial unit (district and subdistrict) over time. A Pearson's correlation coefficient (r) larger than 0.5 and a p-value less than 0.05 implied a good spatial and temporal performance. Spatially, DVIWADI was significantly correlated on average in 19% (4-40%) of districts in Laos (mean r = 0.5) and 27% (15-53%) of subdistricts in Thailand (mean r = 0.85). The DVISE was validated in 22% (12-40%) of districts in Laos and in 13% (3-38%) of subdistricts in Thailand. The DVIBWM was only developed for Laos because of lack of data in Thailand and was significantly associated with dengue incidence on average in 14% (0-28%) of Lao districts. The DVIWADI indicated high vulnerability in urban centers and in areas with plantations and forests. In 2019, high DVIWADI values were observed in sparsely populated areas due to elevated exposure, possibly from changes in climate and land cover, including urbanization, plantations, and dam construction. Of the three indices, DVIWADI was the most suitable vulnerability index for the study area. The DVIWADI can also be applied to other water-associated diseases, such as Zika and chikungunya, to highlight priority areas for further investigation and as a tool for prevention and interventions.

Zika virus outbreak in Brazil under current and future climate.

INTRODUCTION: Zika virus (ZIKV) is primarily transmitted byAedes aegypti and Aedes albopictus mosquitoes between humans and non-human primates. Climate change may enhance virus reproduction in Aedes spp. mosquito populations, resulting in intensified ZIKV outbreaks. The study objective was to explore how an outbreak similar to the 2016 ZIKV outbreak in Brazil might unfold with projected climate change. METHODS: A compartmental infectious disease model that included compartments for humans and mosquitoes was developed to fit the 2016 ZIKV outbreak data from Brazil using least squares optimization. To explore the impact of climate change, published polynomial relationships between temperature and temperature-sensitive mosquito population and virus transmission parameters (mosquito mortality, development rate, and ZIKV extrinsic incubation period) were used. Projections for future outbreaks were obtained by simulating transmission with effects of projected average monthly temperatures on temperature-sensitive model parameters at each of three future time periods: 2011-2040, 2041-2070, and 2071-2100. The projected future climate was obtained from an ensemble of regional climate models (RCMs) obtained from the Co-Ordinated Regional Downscaling Experiment (CORDEX) that used Representative Concentration Pathways (RCP) with two radiative forcing values, RCP4.5 and RCP8.5. A sensitivity analysis was performed to explore the impact of temperature-dependent parameters on the model outcomes. RESULTS: Climate change scenarios impacted the model outcomes, including the peak clinical case incidence, cumulative clinical case incidence, time to peak incidence, and the duration of the ZIKV outbreak. Comparing 2070-2100 to 2016, using RCP4.5, the peak incidence was 22,030 compared to 10,473; the time to epidemic peak was 12 compared to 9 weeks, and the outbreak duration was 52 compared to 41 weeks. Comparing 2070-2100 to 2016, using RCP8.5, the peak incidence was 21,786 compared to 10,473; the time to epidemic peak was 11 compared to 9 weeks, and the outbreak duration was 50 compared to 41weeks. The increases are due to optimal climate conditions for mosquitoes, with the mean temperature reaching 28 °C in the warmest months. Under a high emission scenario (RCP8.5), mean temperatures extend above optimal for mosquito survival in the warmest months. CONCLUSION: Outbreaks of ZIKV in locations similar to Brazil are expected to be more intense with a warming climate. As climate change impacts are becoming increasingly apparent on human health, it is important to quantify the effect and use this knowledge to inform decisions on prevention and control strategies.

Media briefing on COVID-19 - 26/02/2021

00:00:00 FC Shortly. We have simultaneous interpretation in the six official UN languages, Arabic, Chinese, French, English, Spanish and Russian, plus Portuguese and Hindi. Let me introduce to you the participants. Present in the room are Dr Tedros, WHO Director-General, Dr Mike Ryan, Executive Director, Health Emergencies, Dr Maria Van Kerkhove, Technical Lead for COVID-19, Dr Mariangela Simao, Assistant Director-General, Access to Medicines and Health Products, Dr Soumya Swaminathan, Chief Scientist, Dr Kate O'Brien, Director, Immunisation, Vaccines and Biologicals, Dr Bruce Aylward, Special Advisor to the Director-General and Lead on the Act Accelerator, Dr Peter Ben Embarek, WHO Expert on Food Safety and Zoonosis, and joining us remotely is Dr Soce Fall, who is our Assistant Director-General for Emergency Response. Welcome, all. Now without further delay I would like to hand over to Dr Tedros for his opening remarks and to introduce our special guests. Over to you, Dr Tedros. TAG Thank you. Thank you, Fadela. Good morning, good afternoon and good evening. On Monday the Governments of Sweden and Switzerland and the United Nations will host a virtual high-level pledging event for Yemen. Yemen is the world's largest humanitarian crisis with more than 20 million people in need of humanitarian assistance. 00:01:48 More than five million people are now at risk of famine and already half a million children under five could die from hunger in the coming weeks unless they receive urgent treatment. All of this even as the already fragile health system has been left to deal with COVID-19. This current crisis comes at a time after years of conflict when there is now a real opportunity for peace in Yemen. We have to act on it. Two years ago generous funding helped hold off famine. It's time to step up again. The situation now is even more grave. The 2021 response plan includes an ask of US$3.85 billion. I urge donors to be generous. On Wednesday Ghana became the first country outside India to receive doses of COVID-19 vaccine from the COVAX facility and the factory in India, the Serum Institute. Just a few hours ago Cote d'Ivoire received its first doses and more doses will be shipped to more countries in the coming days and weeks as we move towards our target of starting vaccination in all countries within the first 100 days of the year. 00:03:30 We now have 43 days left. I would like to thank our COVAX partners at GAVI, CEPI and UNICEF who have helped bring us to this point and the member states who have provided the resources. We have made progress but that progress is fragile. We need to accelerate the supply and distribution of vaccines and we cannot do that if some countries continue to approach manufacturers who are producing vaccines that COVAX is counting on. These actions undermine COVAX and deprive health workers and vulnerable people around the world of life-saving vaccines. Now is the time to use every tool to scale up production including licensing and technology transfer and where necessary intellectual property waivers and if not now then when? I understand full well that all governments have an obligation to protect their own people but the best way to do that is by suppressing the virus everywhere at the same time. It's also important to remember that although vaccines are a very powerful tool they're not the only tool. We still need to accelerate the distribution of rapid diagnostics, oxygen and dexamethasone. 00:05:08 In that regard we welcome the European Council's statement of solidarity today, committing to contributing the European Union's share of funding to the ACT Accelerator. We must also remember that for more than a year now many countries have successfully prevented or controlled transmission without vaccines and with proven public health measures. On Wednesday WHO officially launched our Strategic Preparedness and Response Plan for 2021 which outlines six objectives and the ten essential pillars of the response. The 2021 SPRP outlines how WHO will support countries in meeting their objectives and the resources we need to do it. Many countries used last year's SPRP as the basis for their national response, adapting and applying it to their own context. One of the countries that has averted a major crisis despite the predictions of various models is Nigeria. With Africa's largest population, its largest economy and its largest city what happens in Nigeria affects what happens in Africa. 00:06:34 Today I'm delighted to be joined by Dr Chikwe Ihekweazu, the Director of Nigeria's Centre for Disease Control and the Head of WHO's Country Office in Nigeria, Dr Walter Kazadi Mulombo. Dr Chikwe is one of Africa's and the world's leading public health experts. My brother, thank you so much for joining us today to talk about Nigeria's experience and response to COVID-19. You have the floor. CI Thank you, my dear colleague and big brother, Dr Tedros, and your team at WHO for inviting me to this important briefing. In Nigeria we are very grateful to WHO at global, regional and local levels - at country level for your support and strong collaboration throughout this response. Tomorrow, 27th February, actually marks exactly one year since Nigeria's first COVID-19 case was detected and since then we've had 150,000 cases with about 1,800 deaths. Although the numbers of cases in Nigeria and Africa have been lower than initially estimated this pandemic has had a devastating impact on our country. Millions of people have been exposed to the direct and indirect impacts of this pandemic. 00:08:19 However, DG, we have learnt many lessons from this response and I though to share only three. Firstly on co-ordination, political leadership has been critical in shaping preparedness and response in Nigeria. In March 2020 His Excellency, Mr President, President Mohammadu Buhari established a presidential taskforce on COVID-19 chaired by the Secretary to the Government of the Federation, Mr Gus Mustafa [?]. This PTF has really provided much-needed multi-sectoral co-ordination, providing clarity of vision and determination in delivery. Secondly I'd like to speak of collaboration. Nigeria's a big country; 200 million people, 37 federal states. Our response has been driven by strong collaboration across federal and state governments, multilateral organisations such as WHO and the private sector, Government and its citizens. So for the public health response we had an emergency operations centre hosted here at NCDC but bringing together all the other partners responding in one room. 00:09:33 Thirdly, DG, I'd like to speak on solidarity. This is a word you have used a lot over the last year and for us this is not just about governments working together but also about communities and individuals playing their part. Our campaign, take responsibility, really struck a chord in Nigeria as we pulled everyone, all Nigerian citizens into our response to become champions of the so-called public health measures; physical distancing, the wearing of masks, hand hygiene and avoiding crowded places. Now to vaccines, DG. We know that despite the best efforts of our Government it will still take a while to get vaccines to everyone. Therefore the solidarity among our population will remain very important throughout the year. In Nigeria our response has always been guided by an incident action plan that is adapted from WHO's Strategic Preparedness and Response Plan and while there's still some uncertainty about the year ahead of us, especially with the emergence of variants of concern, we recognise much clarity on what needs to be done - we recognise that we need more clarity on what needs to be done. 00:10:50 Our success this year will depend a lot on these three things; on co-ordination, on collaboration and on solidarity, whether at country level in Nigeria or globally. We must open up to learning from each other, sharing with each other and working towards global rather than country-level protection. Despite the challenges and hurdles we strongly believe that there are more voices out there that will stand and understand the need for global solidarity with each other. WHO's critical role in all of this is to bring us together; government, academia, private sector, industry; and we'll continue to look forward to WHO's leading role in co-ordinating our efforts. Thank you very much and I look forward to interacting with the rest of you. TAG Thank you. Thank you so much, my brother, Chikwe and thank you for your support, leadership and insight over the past year. At these press conferences every week the world's media see staff from WHO headquarters and our six regional offices also hold their own briefings. What you don't see often enough are our colleagues in WHO's 150 country offices, who are supporting countries every day to prepare for and prevent and respond to COVID-19. 00:12:20 Who does not just parachute into countries when there is an emergency. Our staff are there every day of every year working with the government and communities to address the full range of health threats they face. So today I'm very pleased to welcome Dr Walter Kazadi Mulombo, the WHO Representative in Nigeria. Walter, thank you for joining us and over to you. WKM Thank you very much, DG, for this opportunity to share our contribution to the COVID-19 response in Nigeria. As you know, since the onset of the COVID-19 pandemic and its first reported case one year ago, as Dr Chikwe mentioned, WHO country office has engaged the national authority through the Federal Ministry of Health, the Presidential Task Force and working hand-in-hand with NCDC to develop the tools that would be used later on to galvanise the whole community - donors, partners, the entire Government, the private sector and others - around a common goal, a common objective to prevent the spread, suppress transmission and prevent socio-economic disruption. 00:13:42 So WHO in Nigeria worked alongside the Nigerian CDC. It activated its incident management system alongside NCDC and repurposed all its workforce towards the early moments of the response. For this WHO Nigeria [unclear]. We have a huge field presence with all our staff who have been working on polio and responding to other health emergencies. So we used all our resources to support NCDC and the Government of Nigeria. Also an important dimension to the response is partnerships so we leverage upon the UN country team under the leadership of the UN resident co-ordinator to galvanise all effort within UNCD and to mobilise resources to support the multisectoral resource plan that was put forward by the Government. The UN were able to mobilise over US$73 million that were used to fly into Nigeria supplies, equipment, reagent which were used to save lives and try to control the epidemic from the beginning. 00:15:07 As you know, Nigeria has gone through two waves. There was the first wave, which was brought under control after August and then we had the second wave which started toward early December and which is currently being brought under control. When we saw the second wave WHO worked again with NCDC to conduct an inter-action review both in the capital and in all the states to readjust the strategy and readjusting the strategy has been a consistent strength of NCDC and the Nigerian Government so that the measures we take are commensurate to the risk we identify in the field. So it has been really responsive to the need based on the [unclear] of the epidemic. WHO more recently supported the country to develop its vaccine deployment and vaccination plan for COVID-19. It has been used to secure through the COVAX facility close to 14 million doses of AstraZeneca vaccine, four million of which are expected next week. Nigeria will join other African countries - Ghana and Cote d'Ivoire and several others - to be among those introducing the vaccine during the first 100 days of the year, as you said. So the launch of the new strategic preparedness and response plan by WHO is an opportunity for us to further work with NCDC and the Government to refine again the strategy based on evidence and on science. 00:17:04 I would like to recognise the great contribution and expertise of Dr Chikwe and his team and the whole of Government for an unprecedented commitment which make the WHO or the UN as a whole work even more interesting and a good learning case for other cities. Thank you and over to you, DG. TAG Thank you. Thank you so much, Walter. I send my greetings to all our colleagues in the Nigeria country office and you have my deep thanks and respect. I am very proud of you all and proud to be WHO. Fadela, back to you. FC I would like now to open the floor to questions form members of the media. I remind you that you need to raise your hand using the raise your hand function in order to get into the queue to ask your question and don't forget please to unmute yourself. 00:18:13 I would like also to encourage journalists to take the opportunity of the presence of our two special guests to address questions to them. They will stay with us for the entirety of this press conference. I would like now to invite the first journalist, Christophe Vogt, who is the Bureau Chief, IFP Geneva, to ask the first question. Christophe, you have the floor. CH Good evening. Can you hear me? FC Yes, very well. Go ahead, Christophe. CH Thank you for taking my question. It's to everybody who's there and who might have an opinion on it. The Security Council just voted to improve equitable access to vaccines. The vote just happened 30 minutes ago but at the same time the European Union stated a few days back that they want to vaccinate 70% of their population by the summer. So I was just wondering, are both possible, is it possible to have equitable access to vaccines but at the same time going so much higher than the maybe 20% that is needed to protect the most vulnerable populations? FC Thank you, Christophe. Dr Aylward, you have the floor. 00:19:47 BA Thank you, Fadela and, Christophe, thank you for the question. The resolution that was just passed is important indeed because what it does is it recognises the populations in very special circumstances that may not be reached by vaccines through the mechanisms that have been put in place to ensure equitable access around the world, especially targeting, as we've talked about previously, first healthcare workers and then older populations and then people who have comorbidities and other conditions, as we've spoken about. Of course these people can be found anywhere, in any country whether in the wealthy countries or the lower-income countries but also places affected by conflict and other circumstances which make it very difficult to reach them. So this is an important resolution because it recognises the need; it's a key piece of the equitable access framework. Of course for equitable access WHO, COVAX, all of our partners whom we work with still promote that all populations need to roll this vaccine out together. We need to get to the healthcare workers around the world together, then we need to get to the older populations, as we said, and beyond. 00:21:05 So if we have enough vaccine to do that... No, we don't right now in the world and so we are still calling very much for the equitable distribution of what continues to be a very scarce resource so that we can reach all of those populations in that right order. There is certainly enough vaccine in the world right now to be able to reach those highest-risk populations in all countries, in all areas and the challenge remains for all of us working together to make sure it is distributed equitably, as you highlight. FC Thank you. I would like now to invite Simon Ateba, Africa News Today, to ask the next question. Simon, you have the floor. SI Thank you for taking my question. This is Simon Ateba for Today News Africa in Washington DC. My question is to Dr Chikwe Ihekweazu, the Director-General of the Nigeria Centre for Disease Control. Director-General, as you said, Nigeria has recorded more than 154,000 cases of COVID-19 and over 1,800 deaths, the highest death toll in West Africa. That's still very small when compared to the rest of the world. Still, most people who contracted the virus in Nigeria have recovered. Can you explain why the recovery rate has been so high in Nigeria and how many people will Nigeria vaccinate since it's a big country of 200 million plus people? What's the vaccine acceptance like in Nigeria? Thank you. 00:22:46 FC Dr Chikwe, you have the floor. CI Thank you very much. I missed the very last part but I'll start from the beginning. When we started this response of course the whole world expected the continent of Africa and Nigeria with our population realities, our socio-economic realities to basically fall apart. So I think one of the reasons has to be that we did actually mount a very strong response in the beginning, took some very hard decisions in our country to lock down the economy fairly early, shut down international travel, stop all domestic travel. These were very hard decisions for our Government to make. They made those decisions in the best interests of our people and enabled us the time to build the response. 00:23:38 But even from the beginning we were very clear and our leadership was very clear that shutting down the economy is not really an ideal outbreak response and that was done because we needed to prepare the public health workforce to be able to respond more effectively. Then what really happened was that there was a real mobilisation of people across the country to take responsibility for the future of our country and so the public health measures that we speak about were really for a long time adhered to before some people got tired later in the year and we carried out an effective public health response. The things that might be new to some people; the details of contact tracing, identifying cases, isolating them; we'd unfortunately had the opportunity to do this severally for many outbreaks that we've faced in the past so it wasn't new to us. We mobilised our resources fairly effectively to deliver on this and thankfully we have the numbers that we have. But just recently we carried out a seroprevalence survey in four states in Nigeria and in Lagos State for instance we found a seroprevalence of 23%, of course with confidence intervals around that, meaning that there must have been a lot more infection than we had found through our surveillance system, meaning that there were a lot more mild cases of infection. 00:25:10 This might be as a result of the very young population in Nigeria. So there are many things that drive the response that we are still learning but the key thing is, unlike previously, we are part of the science, we're part of the discovery. We're learning as we're doing, we're iterating and using what we learn to shape the response in real time and that really is one of the most important parts of this response. Working together with WHO and with all our partners we have been active participants in our own destiny and not reliant on just support from the outside because the borders were closed anyway and we couldn't get as much support globally as we would normally have. On the second question on the number of people we intend to vaccinate, like every country in the world we want to vaccinate as many people as possible. That's a legitimate desire by any country and that's the same here but we also recognise the need for equity in distribution of access and that's why we have aligned very strongly with the African Union and Africa CDC's approach because even within the continent there are also differences in countries' abilities to support their citizens. 00:26:29 But Nigeria has been very firm in saying that we will not look for bilateral deals, we will work in a multilateral way with WHO, with COVAX, with the African Union to make sure that as we get vaccines into Nigeria the same happens in Benin [?], in Togo, in Ghana, in Cote d'Ivoire, in Senegal, in Ethiopia, across the continent. So we're working very hard to get as many vaccines as we can get into Nigeria, at the same time working with our brothers and sisters across the continent to enable them to get it [?] as well. So we're looking forward to our first deliveries. We've looked at the deliveries in Ghana and Cote d'Ivoire with a bit of excitement but also a lot of desire. We want to see the same happen in Nigeria over the next few days as the biggest country on the continent and I think getting the outbreak under control in Nigeria will serve the continent well, it will serve the world well and we look forward to receiving those vaccines soon in our city, in our country's efforts. 00:27:35 FC Thank you, Dr Chikwe. I would like now to invite Jamie Keaton, Associated Press in Geneva, to ask the next question. Jamie, you have the floor. JA Thank you, Fadela, thank you so much. Nice to see you all. As you may know, Pope Francis is scheduled to make a four-day visit to Iraq starting a week from today. There are expected to be masses both indoors and outdoors and trips to various parts of the country are expected to draw large crowds. The Vatican delegation and accredited media are all vaccinated but the Iraqis most at risk are not and Iraq recently went into a modified lock-down with schools and mosques closed and a night-time curfew due to a surge in cases, many of those linked to the variant that emerged in the UK. So my question; can you remind us of WHO's advice about mass gatherings, especially in countries facing severe outbreaks and the epidemiological wisdom of such a high-profile visit that is likely to draw big crowds? 00:28:51 What would you advise the Vatican about ways to ensure that it will not inadvertently provoke a super-spreader event? Thank you so much. FC Jamie, you are talking about Iraq. JA Correct. FC Yes. MK Thanks for the question. WHO has issued guidance on mass gatherings, whether these are gatherings that are planned or gatherings that are spontaneous, taking a risk-based approach. It depends on a lot of different factors that are happening with the country in terms of the epidemiological situation, the handling of the event itself in terms of if it's indoors, if it's outdoors, the nature, how many people will be the, if there can be physical distancing, the use of masks, etc, if there's a plan in place what the event-holders will do in the case of someone who is sick, someone who's symptomatic, someone who's a case, how they can carry out all the necessary public health actions. We have issued this advice many, many months ago, which all countries are using to take a risk-based approach on those decisions on if an event can happen and if so how it can happen safely and if not if that event can be postponed. 00:30:09 This is the same for mass gathering events that are large and it's the same advice we would give for gatherings that are happening at people's homes; if they're having birthday parties for example. It's all about managing that risk so there is no one short answer of if an event can be held or not. It's about looking at the epidemiologic situation in the country and then making sure that if that event is to take place that it can take place as safely as possible. FC Thank you. I would like now to invite Sara Teofilo from Coreo, Brazil to ask the next question. Sara, you have the floor. SA Hi. Thank you for taking my question. Brazil is having its worst moment during the pandemic with a high number of deaths and a lack of ICU beds in several states. The occupancy rate of ICU beds is above 90% in many of them. I wonder if you can blame the new variant for the collapsing health system and if increasing ICU beds is enough to solve the problem. Thank you. 00:31:28 MR I didn't quite hear all of your question but I think we spoke on this last week, both Mariangela and myself, that not all countries were in a downward trend and there was a persistent trajectory of cases in Brazil and certainly we haven't seen a prolonged downward trajectory. Mariangela explained at that time that there were different trends happening in different parts of Brazil. It's a very, very large country in a complex situation but there's no question that Brazil is not the only country facing this situation. There are many countries in which the downward trend is not... There are many countries thankfully where that is happening and there are many countries in which that downward trend is not being achieved. The contribution of variants to that situation is not fully understood in this particular case. What we do know in countries that are applying persistent and consistent measures in terms of public health and social measures and individual behaviour; that that is affecting the trajectory of all variants and even though some variants have shown a propensity for higher levels of transmission what is clear is that the control measures that have been designed are effective in driving that down. 00:32:47 We've seen in the past that just ramping up health systems' capacity is not enough. Your health system will be overrun if the force of infection; if the trajectory of cases is rising and your health system cannot cope today it will certainly not cope tomorrow if that pressure continues in the system. So yes, it is always good to shore up health capacity, it's always good to be able to open more beds and to move health workers from areas under less pressure to support staff in other areas. All of that is good but that in itself is not enough; you have to get to grips with the transmission as it's occurring at the community level and many parts of Brazil have suffered intense community transmission over a very prolonged period of time. It's been very tough for Brazilians and for Brazil in general and ait is very difficult in a populous country where people are very often living in multi-generational, multi-family homes, many living in periurban areas where poverty and lack of access is a major issue. 00:33:52 So it is easy to sit here and talk about what should be done; it's very difficult in reality to achieve that in some of the settings that the Brazilian authorities face and the communities themselves face but there is no other way. The only way out of this is to do that work. You heard Chikwe and congratulations, Chikwe; we have tremendous admiration. Nigeria is a very similar set-up; a large country with large urban areas and they really had to come to grips with some very, very difficult decisions and to remain cohesive and persistent in the application of those measures while taking into account and recognising the economic and social toll of that and finding the balance between those measures to keep the rates of transmission at a low enough level to prevent the health system becoming overwhelmed. So many countries have faced that reality. Unfortunately - and it is a tragedy for Brazil that Brazil is now facing that again and it is tough. This is the fourth time around for Brazil, I think, at least and the situation in Brazil has improved in some areas while it's disimproved in others so I don't think there's been a point in the last year where some part of Brazil has not been deeply affected by this pandemic. 00:35:05 So it is very tough and we should take a moment to show solidarity with the people of Brazil and to provide the necessary aid and support needed for them to be able to come to grips with this disease. But again Brazil is a very able country and has many fantastic public health and scientific institutions and I think Brazil knows what to do and many states are trying to apply the best measures but it's not straightforward, it's not easy. But I think it's a lesson now for all of us that this is not over; it's not over for anybody and any relaxation of our resolve is dangerous and we need to, as I say, be very aware; this virus still has a lot of energy and if the measures we apply are not persistent, comprehensive and aimed at continuing to suppress transmission while introducing vaccines we will pay a price and unfortunately our communities will pay a price as well. MK Very briefly I just want to take an opportunity to mention the variants because the question also said, is it due to the variants? You've heard us say that there are variants of concern that have been identified from some countries. 00:36:20 WHO actually issued some definitions yesterday on our website in our weekly epidemiologic update which outlines proposed working definitions. I say working definitions because these may change over time as we learn more about them but these are working definitions of variants of interest as well as variants of concern. This is mean to help guide countries in looking at the viruses that they are detecting in their countries and looking at the full genome sequences that are being conducted by countries to see if there are any changes in these viruses and using these definitions what actions they need to take to report to us, what studies need to be done in country. We've set the threshold for determining a variant of interest very low so that they're sensitive enough to capture potential important variants but we've also set the threshold for the determination of a variant of concern very high so that we can focus the attention and resources on variants with the highest public health potential. 00:37:24 This is important so this is on our website; we will provide the link in the chat below so that you can see this. We expect that there may be some modification of these definitions over time but this is meant to be a helpful guide to determine which of these mutations, which of these variants are interesting in the sense that they may have some public health importance, some public health impact potentially on some of the countermeasures as we go forward. This is a system that needs to be in place as we go forward as this pandemic evolves. Some of the virus variants that have been detected, the virus variants the WHO is tracking have shown some increased transmissibility and if you have increased transmissibility it means you have more cases. If you have more cases this means you could have more hospitalisations which could put some burden on the healthcare system and in some countries the healthcare system is overburdened to begin with and this could lead to an increase in severity and death. So we want to make sure that the measures that are in place are preventing as many infections as we can. So far based on all of the variants that we have seen, that are being tracked the public health and social measures, the infection prevention and control measures in health facilities and outside of health facilities work against these virus variants that are circulating. 00:38:44 We are seeing this in country after country as incidence declines. We are seeing this directly from studies that are being conducted in countries that have these virus variants that are predominantly circulating and this is good news. But we need to continually monitor this so we have a system, a global system in place to not only identify which of these mutations are important but what they mean in terms of transmission, in terms of severity and in terms of any potential impact on available and future diagnostics, therapeutics and vaccines. We are working with partners all over the world, in country as well as public/private partnerships with all of the different manufacturers to make sure that we can monitor these almost in real time. That is difficult because it takes time to do some of these studies but we are very grateful for all of the collaborations around the world and the institutions that are helping us track and monitor these. So do look on our website related to these definitions and we will be providing weekly updates in our sit reps that we release every week on our WHO website summarising what is being tracked globally. 00:40:02 FC Thank you. I would like now to invite Jeremy Launch from Radio France Internationale, RFI, to ask the next question. Jeremy, you have the floor. JE Thank you, Fadela. I'd like to go back to what you said at the beginning and what you're currently saying at every press conference; the fact that you're asking countries not to go directly to the manufacturers to get more supplies and bypass COVAX. My question may be blunt but is anyone listening, do you feel any country is actually listening? Because we hear every week - last week again the EU is getting more doses from Moderna. So do you actually have one example of one country that's saying, okay, we get it, we're not going to do it any more? Are you confident about next week's proposal at the WTO about the intellectual property waiver that could be a major success for COVAX? Thanks. 00:41:10 FC Dr Aylward, you have the floor. BA Thank you very much. I think I counted four questions but the key one is, are countries listening about the importance of making sure that we do not interrupt the supply inadvertently to other countries. Absolutely, countries are listening. It was a bit of a free-for-all quite frankly a few weeks ago and months ago as countries were pursuing deals that could have compromised the supply through COVAX. There are still conversations ongoing, yes, very much so but countries are definitely listening, which was your first question; countries are definitely listening. Some countries are still pursuing deals that will compromise the COVAX supply, without a doubt so while, let's say, all countries are listening not all are acting on what we are asking for and that is that they respect the supplies to COVAX. Some of the major suppliers to COVAX like the Serum Institute of India in particular, as the Director-General said, are being approached by multiple countries that had not originally intended to supply from that site and as that site was originally thinking to supply COVAX and to supply India any other demands on it do put a strain potentially on the supply, to be very frank. 00:42:39 But your first question was the most important one; are they listening? I think probably the Director-General's highlighting of this issue and others'... Yes, they are and I think that's great but once again I think we have to recognise every country's just under tremendous strain and demand. It's tough. Politicians, as Mike and the Director-General have said repeatedly, are under incredible expectation from their populations to deliver vaccines as rapidly as possible and what we have to remember is that's not politicians in just some countries; it's everywhere and what we need to ensure is that the health workers and then the older people in populations and then of course those with other risk factors receive vaccine as rapidly as possible. So people are listening, some are acting on that, we hope more will and just over the last few days we've been able to lock in through the COVAX facility and the great work being done by GAVI, UNICEF and others, through all that partnership been able to lock in the volumes that we're going to need over the coming weeks. 00:43:42 But there's never enough supply, quite frankly. We need more countries acting in support of COVAX as we go forward. The last point you raised about what will happen at the WTO next week; I don't think anybody's confident about what the outcome will be so I think next week we'll all hear. Again what we're encouraging all countries and companies at this point is to be doing everything possible to expand their production. That's going to require a range of solutions, as the Director-General highlighted. The most successful and rapid way, we believe, to expand production is through technology transfer; sharing the know-how, through voluntary licensing if needed with other manufacturers that can fill and finish product, that can produce product. That is usually the most successful way to do it. It's when that fails and we're in an emergency like this and we can't expand production that people want to look to other measures. 00:44:42 FC Dr Simao, you have the floor. MS A very quick complement on the TRIPS waiver. We heard earlier today a question about the Security Council and WHO very much welcomes that the discussion around the provision and making equitable access a reality is happening in different bodies at the UN so we very much welcome the discussion on the TRIPS waiver at the WHO TRIPS council. That said, just complementing because of course intellectual property is always a very sensitive topic in anything that's related to access to medicines and to vaccines and other health products and we're living through a situation where there's an extreme concern by countries looking for alternatives to increase production capacity. Of course this includes how to manage the intellectual property rights and this could be managed through various forms including through voluntary licence, as Dr Aylward mentioned. Just to say that WHO does co-ordinate the COVID Technology Access Pool which is working with 44 countries now to include not only the sharing of technology but also the voluntary licensing of the technologies that can help us to address the acute phase of this pandemic. 00:46:18 So of course we are very interested in the outcomes of this discussion at the TRIPS council, as we welcome any movement from countries to decrease and to address current barriers to access and also barriers to access that could be seen at mid and long term so this is quite an important discussion. Thank you. FC Thank you, Dr Simao. Dr Ryan. MR Just a very short point; I think we need to continue to close the gap between the rhetoric and the reality and I believe there's a healthy debate going on in many countries and that's great but there are some countries where there isn't even a debate. I'm afraid, as the old adage says, you can't have your cake and eat it too. I'm afraid some countries think that they can. FC Thank you. I would like now to invite a journalist from BBC Africa. I hope I pronounce your name well, Charles Mbunu. Charles, you have the floor. CL Thank you. That was a good effort; you tried. Thank you. My question is to Dr Chikwe. I just wanted to know; you've mentioned that the vaccines are expected in a few days. I want to know because there have been questions about storage of this vaccine and more general handling of the vaccines. How confident are you that there is enough facility on the ground or if there is enough facility on the ground to handle the storage of these vaccines? 00:48:03 Also what's the plan in terms of the other vaccinations? We are seeing in local media that politicians may be given vaccines ahead of others, perhaps health workers so just help to clarify that. Thank you. FC Dr Chikwe, you have the floor. CI Yes, thank you very much. The whole country really is looking forward to the vaccines, that's for sure but having said that, we've had many challenges in Nigeria but some of those challenges have also brought opportunity. Last year we finally eliminated wild polio virus in Nigeria and therefore on the African continent. 00:48:47 It meant that over the last few years I don't know any country that has done more vaccination campaigns than Nigeria. The people involved in doing micro-planning, delivering of the vaccines, planning logistics; they do this in their sleep. We have an agency responsible for this, the National Primary Healthcare Development Agency. They have a well-fuelled system delivering to the states, then the states to the facilities and all of these have been in preparatory mode for the last few weeks, working very hard to cross the Ts and dot the Is. So we were very anxious when it looked as if we would get the Pfizer vaccines in the beginning because of obvious challenges around storage outside of our major cities but once it became clear that the first set of vaccines would be the AstraZeneca Oxford vaccine we became fairly confident that with the infrastructure we have, with the human resources that we have and with the delivery... Nigeria; we deliver at critical times so we are confident that we will be able to do this. On your second question on prioritisation, everyone - I think we would be remiss to get this wrong. Every country; people are looking. We have a very open, vibrant media space. Government has actually been very transparent in the work that we've done. We've been very open in communicating to Nigerians and globally in terms of our challenges and opportunities so we've been clear; we will prioritise our healthcare workers absolutely first. 00:50:36 There will be some others prioritised for various reasons but I think we must trust the leadership around this. We're making some very hard decisions. I think at the end of the day the key thing is we all recognise that we can only impact on transmission and reduce the burden on our hospitals if we target the right people initially at the right pace and at the right distribution. So everything will come into play, not only the priority population groups but geography as well. We have a very uneven outbreak in Nigeria. Lagos State for instance has 40% of all the cases in Nigeria so it won't be a surprise if they are prioritised to such an extent but at the same time we need to get some vaccines to every state in Nigeria. So it's a big country, a complex country but a lot of detailed planning is going into ensuring that the vaccines get to the right people as quickly as possible so that we can get the outbreak under control in Nigeria. 00:51:45 FC Thank you, Dr Chikwe. Dr Kazadi Mulombo, if you want to speak you are welcome any time. WKM Regarding the preparation and the prioritisation, the healthcare workers are the first priority for this first batch of the vaccines and then there are actually four stages in this vaccination so the health workers are definitely the priority. Then we have people with underlying conditions which is the next priority, then the elders and the other groups including those living in IDP camps and vulnerable populations and those working in difficult-to-reach areas where we could use our experience with polio to reach the outer areas and to reach those who are currently living in inaccessible areas due to some security concerns, as you know. WHO, UNICEF, the World Bank and other UN agencies have been working hand-in-hand with the Government. We are part of the planning, we are monitoring and we are ready to continue to support the country to roll out the vaccine in an as equitable as possible way so that we can achieve the benefit of the vaccine. If we are able to vaccinate enough to get the necessary coverage and achieve herd immunity that would be great but for this year, 2021 we are targeting 40% of the population, 20% coming through the COVAX and an additional 20% through Government funding. 00:53:49 The donors are prepared to chip in and help Nigeria get all the support needed including for operational and logistics. FC Thank you so much. I would like now to invite John Zaracostas from France 24 English service to ask maybe the last question. John, you have the floor. John, can you hear me? You are unmuted, John. JO Fadela. FC Yes. JO Okay, good. My question is to Dr Ryan and to Maria on the podium. I don't want to sound like a Cassandra on a Friday evening but is there a black swan situation where we could have a second pandemic threat in parallel with the current pandemic? 00:54:56 My concerns were raised about the Russians notifying to the WHO the new cases of H5N8. FC Thank you, John. MK Hi, John, nice to hear your voice. There are possibilities and there are possibilities. WHO, as you know, is an organisation that is constantly looking at the potential pandemic threats from a large number of known pathogens as well as new pathogens. This is why we have a health emergencies programme. This is why we work on preparedness and response and why we have people all over the world who are setting up surveillance for known pathogens and viruses and the unknowns. We work very closely with our partners at FAO and OIE to be tracking different viruses in animals that have the potential to spill over into human populations. What we do is we work in countries to make sure that we have good surveillance in place for rapid detection, for early rapid response and making sure that we have systems in place, laboratories in place, public health systems in place to be able to detect and respond and act. You have an excellent example today in Nigeria with our WR, our WHO Representative and Nigeria CDC showing that years of preparedness for infectious diseases are put to good use for the latest disease X, which happened to be COVID-19, SARS-CoV-2, the virus that causes COVID-19. 00:56:34 So we are always looking at the possibilities that there could be additional threats against our planet, against the human race and of course there may be. We have a flu division, our global influenza programme that are tracking influenza viruses, seasonal influenza viruses, looking at avian influenza viruses constantly. That work has not stopped. We have teams that are looking at nipah viruses, that are looking at Ebola viruses, that are looking at lassa, that are looking at chikungunya and zika; I could go on and on. That work doesn't stop and I think it's important to mention - I'm giving a long answer here because you hear us speak a lot about COVID-19 but there's work by WHO and our thousands of staff around the world in our 150 country offices and our six regional offices as well as our partner agencies and ministries of health, ministries of agriculture, ministries of the environment that are constantly on the lookout. 00:57:33 So yes, there's laws the possibility that there could be additional threats but what is important is that we have those systems in place and that we use the time right now and this traumatic experience that all of us are in for COVID-19 to make sure that we don't lose sight of what could happen in the future and we're building back systems that are sustainable for any infectious threat that could come our way. We are tracking this H5N8. There was a disease outbreak news that was released a few days ago looking at some asymptomatic cases in Russia. Our flu team this week is actually discussing vaccine composition for the next influenza season so all of this work is happening in the background. You don't get to see them up here every day but they will be releasing their findings from that deliberation this week. So yes, we are constantly tracking these and you will hear about this through our disease outbreak news and we will follow up with any advice that is necessary as quickly as possible. MR Just to maybe add that WHO is announcing the recommendations for influenza strains to include in the vaccines for the 2021/2022 northern hemisphere season and again expressing huge gratitude to the hundreds of labs in the network who constantly track the evolution of influenza viruses around the world including the genetic sequencing and characterisation of those viruses both epidemiologically and clinically, which leads to the instructions to the manufacturers for the best components for vaccines every six months. 00:59:15 That process is in place and we're looking to create a very similar and linked system for SARS-CoV-2 as well so the world is being well watched over in that regard but again reflecting on the power of partnership between scientific institutions, the power of our member states and partners, public and private sector, who work together constantly to keep the world safe from influenza. It's more important than ever; the current pandemic has led to... In effect, the same measures that have stopped SARS-CoV2 have also effectively suppressed transmission of influenza. That means there's a lot of potential energy left in the influenza virus, especially as normal and natural immunity will wane. So there will be at some point a rebound in influenza so it's exceptionally important that we continue to work on that and that we reiterate that influenza vaccination remains the best tool for prevention of influenza and we should plan now while we're procuring vaccines for COVID-19; it's very, very important. 01:00:21 But also governments need to continue to plan for their influenza season and remain vigilant for influenza in all its forms. Part of the reason for tracking the avian strains - and this again reflects a tremendous amount of work that goes on in tracking these viruses that cross the species barrier mainly through avian strains. The virus associated with the H5N8 incident in Russia is currently being fully characterised and part of that process with industry and with the WHO collaborating centres is to constantly produce candidate vaccines. We talk about vaccine production happening for SARS-CoV-2; it's very important. But remember, there are manufacturers out there and our collaborating centres who as soon as there's a signal of a new virus or a virus with potential to infect humans immediately begin to produce potential vaccine lots so that if we see any shift towards human transmission or towards an epidemic in humans of a new virus we have the immediate capacity to begin scaling up vaccine trials and vaccine production. This is really, really important health security work. 01:01:36 Just while I have the floor to say to Dr Chikwe that Nigeria's Centre for Disease Control and your personal leadership there both in public health and in science reflects something, I think, that's not recognised globally. I look to Dr Chikwe in Nigeria, to Dr Sakoba, the Head of the National Agency for Health Security, who's leading the fight against Ebola in Guinea, to Drs Moembe and Sabwe and Ahuka in INRB in DR Congo, who co-developed the monoclonal antibodies that are now curing this disease in Guinea. The leadership, Dr Chikwe, you've shown in developing the research roadmap for lassa fever and all of those other diseases... There is a perception out there that disease X and all of these sophisticated emerging diseases are being responded to and all of the science is happening in the north. That is not true. The first line of defence is in the areas most at risk, in the areas of high biodiversity, in areas where this disease can cross the species barrier and it is to the great comfort of the world to know that there are such wonderful scientists working in the front line who understand how to do this business extremely well and I think we need to do more of that. 01:02:59 We need to build the capacity, to understand the tech, to characterise and develop countermeasures as close as possible to the point of emergence and we need to invest in institutions like the Nigeria CDC and in individuals and science and public health leaders in these countries who do an amazing job with very little resources. I also congratulate Austin Demby, who's the new Minister of Health in Sierra Leone, who himself has a massive historical background in the study of emerging diseases. I don't know if there's ever been such a concentration of expertise in any given subregion of the world of true leaders in the area of science and emerging diseases and I think it's a wonderful thing for us to be able to recognise today. FC Thank you, Dr Ryan. We have gone over one hour since we started this press conference. Before handing over to Dr Tedros I would like to invite our guests if they have any final comment to make; over to you, Dr Chikwe or Dr Kazadi Mulombo. You have the floor. 01:04:10 CI Thank you very much. I'll start; then my brother, Walter, will close. Just to say thank you very much. There've been discussions about the role of WHO at various points in this outbreak and I think for us on the African continent it's unfathomable for anyone to even think about minimising the role this organisation plays to pull us together, to hold us together, to guide us as we develop our own capacities to look after ourselves, which we've been doing over the past few years. I think the way this outbreak and pandemic has panned out has really brought to life how interdependent we are on each other. When we spoke about this in the field previously it seemed like a hypothetical scenario but this outbreak has really shown, whether you're in the north of the world or in the south, west, east, rich, poor, we are all at risk and it's in our own individual best interests to make sure that all of the world is protected against the threats that we face. 01:05:17 So as we get to the point of rolling out immunisation, vaccination campaigns in our countries and we focus on the tools that might take us to the end of this outbreak it's important that we don't lose focus on the broader issues, on how we collectively think about how to make our world a safer place for all of us. Walter. FC Thank you, Dr Chikwe. WKM Thank you again, DG, and thank you, my brother, Dr Chikwe. To close this session I would like to recognise the type of relation I can see between WHO and the Nigerian CDC and even the Government. Their relationships are very strong and WHO is really a trusted partner, particularly when it comes to ensuring that co-ordination is effective among several players. When I resumed in June last year that was the main assignment I was given by the authorities; to ensure that there is co-ordination among players and we believe as WHO so far we played that role. We managed to rally many stakeholders, private sector, the government, the community around one purpose; to suppress transmission and to save lives. We've learned a lot so far through this pandemic response and we think there is now an opportunity. It's time to re-engineer the health security agenda and the way we implement it alongside universal health coverage as the other side of the same coin, like DG Tedros used to say. Thank you so much for this opportunity to share our experience.01:07:20 TAG Thank you. Thank you, Chikwe; thank you, Walter. Thank you so much indeed. Maybe I would like to say a few things given the UN Security Council's vote earlier today. We can't beat COVID without vaccine equity. Our world will not recover fast enough without vaccine equity; this is clear. So sharing the vaccine which is being produced is actually the best way to bring lives and livelihoods back to normal. So it's in the interest of all countries to co-operate. In terms of vaccines especially there is what they call an elephant in the room; some of the measures we need to take. For instance the sharing problem can be addressed effectively if production is increased and to increase production there are trade barriers or other barriers that have to be addressed. I think a good number of them have been listed before; could be technology transfer, could be voluntary licensing and temporary waiver of intellectual property. 01:09:08 Especially when temporary waiver of intellectual property is raised we see lack of co-operation and even serious resistance. To be honest, I can't understand this because this pandemic is unprecedented. The virus has taken the whole world hostage. This thing happens probably once in 100 years and in the TRIPS agreement there is a provision for a waiver of intellectual property but there are people who don't even want to discuss this issue. If this provision cannot be applied now then when? If we cannot apply provisions for a difficult time like now, during unprecedented conditions then when? I think this is serious. I'm glad the UN Security Council has voted in favour of vaccine equity and at the same time if we're going to take practical solutions then waiver of intellectual property should be taken seriously and the UN Security Council can do it if there is political will. Voting for vaccine equity is important and we appreciate that but the concrete steps should be taken and waive intellectual property to increase production, increase coverage of vaccine or immunisation and get rid of this virus as soon as possible. If we're going to suggest in concrete terms I think this is one. Of course we should not just focus on this. There are also other practical steps that can be taken and where the UN Security Council has a big influence and bring vaccine equity as soon as possible to defeat this pandemic. 01:12:05 So the choice is in our hands. This is something that can be done. I repeat again; if it cannot be done now in unprecedented times, in times of crisis like this that happen once in 100 years maybe, when is it going to be used, when? I hope we will make the right choices and in addition to the voting we take concrete action. Thank you so much and I would like also to thank Fadela. She has been moderating our pressers for some time now. Her and her colleagues do it in rotation so one of her colleagues will come to help, Christian, but I would like to use this opportunity to thank Fadela in a big way. Thank you so much; Shukran jazeelan, Fadela. FC Thank you, Dr Tedros. I would like to thank also our journalists who follow us very regularly. I remind you that we will be sending the DG's opening remarks plus the audio file as soon as we finish here. The full transcript will be posted on the WHO website tomorrow. Thank you for the opportunity of moderating these press conferences for the last five months. I'm sure you are in very good hands with my friend and colleague, Christian Lindmeier, as of next week. Thank you all and have a nice weekend. 01:13:52

Complications and Sequelae in Patients With Congenital Microcephaly Associated With Zika Virus Infection: Two-Year Follow-Up.

BACKGROUND: We aim to describe the long term follow-up of a cohort of children exposed in utero to the Zika virus. METHODS: Descriptive study of a cohort of microcephalic children due to Zika virus. Logistic regression was used to evaluate variables associated with worse prognosis epilepsy. RESULTS: We followed 28 children (15 females), with a median follow-up of 24 months (IQR = 12-28). During the follow-up, 1 infant died. The median head circumference at birth was 29 cm (IQR = 27-31). All presented a global developmental delay. The most frequent central nervous system abnormalities were on cortical development in 22 participants; dysgenesis of corpus callosum in 13; ventriculomegaly in 25; and calcifications in 24. A total of 9 presented ocular abnormalities, 4 auditory impairment. During follow-up, 12 presented with sleep disorders, 10 with irritability, and 23 with epilepsy (2 with generalized tonic-clonic, 3 with generalized tonic-clonic and spasms, 12 with spasms, 3 tonic and spasms, and 3 motor focal and spasms). The median age at the begin of the epilepsy was 4 months (IQR = 2-10), the median number of drugs used to control the epilepsy was 2 (IQR = 2-3). Maternal illicit drug use during pregnancy was associated with worse prognosis epilepsy (Lennox-Gastaut syndrome, West syndrome, or status epilepticus). A total of 19 presented with dysphagia, 10 children required gastrostomy. CONCLUSION: Children with microcephaly due to Zika virus presented with several complications during follow-up, as epilepsy, spastic diplegia, and global developmental delay.

Cohort profile: Study on Zika virus infection in Brazil (ZIKABRA study).

Zika virus (ZIKV) has been detected in blood, urine, semen, cerebral spinal fluid, saliva, amniotic fluid, and breast milk. In most ZIKV infected individuals, the virus is detected in the blood to one week after the onset of symptoms and has been found to persist longer in urine and semen. To better understand virus dynamics, a prospective cohort study was conducted in Brazil to assess the presence and duration of ZIKV and related markers (viral RNA, antibodies, T cell response, and innate immunity) in blood, semen, saliva, urine, vaginal secretions/menstrual blood, rectal swab and sweat. The objective of the current manuscript is to describe the cohort, including an overview of the collected data and a description of the baseline characteristics of the participants. Men and women ≥ 18 years with acute illness and their symptomatic and asymptomatic household contacts with positive reverse transcriptase-polymerase chain reaction test for ZIKV in blood and/or urine were included. All participants were followed up for 12 months. From July 2017 to June 2019, a total of 786 participants (284 men, 502 women) were screened. Of these, 260 (33.1%) were enrolled in the study; index cases: 64 men (24.6%), 162 (62.3%) women; household contacts: 12 men (4.6%), 22 (8.5%) women. There was a statistically significant difference in age and sex between enrolled and not enrolled participants (p<0.005). Baseline sociodemographic and medical data were collected at enrollment from all participants. The median and interquartile range (IQR) age was 35 (IQR; 25.3, 43) for men and 36.5 years (IQR; 28, 47) for women. Following rash, which was one of the inclusion criteria for index cases, the most reported symptoms in the enrollment visit since the onset of the disease were fever, itching, arthralgia with or without edema, non-purulent conjunctivitis, headache, and myalgia. Ten hospitalizations were reported by eight patients (two patients were hospitalized twice) during follow up, after a median of 108 days following symptom onset (range 7 to 266 days) and with a median of 1.5 days (range 1 to 20 days) of hospital stay. A total of 4,137 visits were performed, 223 (85.8%) participants have attended all visits and 37 (14.2%) patients were discontinued.

Broad-Spectrum Antiviral Activity of 3'-Deoxy-3'-Fluoroadenosine against Emerging Flaviviruses.

Emerging flaviviruses are causative agents of severe and life-threatening diseases, against which no approved therapies are available. Among the nucleoside analogues, which represent a promising group of potentially therapeutic compounds, fluorine-substituted nucleosides are characterized by unique structural and functional properties. Despite having first been synthesized almost 5 decades ago, they still offer new therapeutic opportunities as inhibitors of essential viral or cellular enzymes active in nucleic acid replication/transcription or nucleoside/nucleotide metabolism. Here, we report evaluation of the antiflaviviral activity of 28 nucleoside analogues, each modified with a fluoro substituent at different positions of the ribose ring and/or heterocyclic nucleobase. Our antiviral screening revealed that 3'-deoxy-3'-fluoroadenosine exerted a low-micromolar antiviral effect against tick-borne encephalitis virus (TBEV), Zika virus, and West Nile virus (WNV) (EC50 values from 1.1 ± 0.1 µM to 4.7 ± 1.5 µM), which was manifested in host cell lines of neural and extraneural origin. The compound did not display any measurable cytotoxicity up to concentrations of 25 µM but had an observable cytostatic effect, resulting in suppression of cell proliferation at concentrations of >12.5 µM. Novel approaches based on quantitative phase imaging using holographic microscopy were developed for advanced characterization of antiviral and cytotoxic profiles of 3'-deoxy-3'-fluoroadenosine in vitro In addition to its antiviral activity in cell cultures, 3'-deoxy-3'-fluoroadenosine was active in vivo in mouse models of TBEV and WNV infection. Our results demonstrate that fluoro-modified nucleosides represent a group of bioactive molecules with excellent potential to serve as prospective broad-spectrum antivirals in antiviral research and drug development.

Zika virus transmission by Brazilian Aedes aegypti and Aedes albopictus is virus dose and temperature-dependent.

BACKGROUND: Zika virus (ZIKV) emerged in the Pacific Ocean and subsequently caused a dramatic Pan-American epidemic after its first appearance in the Northeast region of Brazil in 2015. The virus is transmitted by Aedes mosquitoes. We evaluated the role of temperature and infectious doses of ZIKV in vector competence of Brazilian populations of Ae. aegypti and Ae. albopictus. METHODOLOGY/PRINCIPAL FINDINGS: Two Ae. aegypti (Rio de Janeiro and Natal) and two Ae. albopictus (Rio de Janeiro and Manaus) populations were orally challenged with five viral doses (102 to 106 PFU / ml) of a ZIKV strain (Asian genotype) isolated in Northeastern Brazil, and incubated for 14 and 21 days in temperatures mimicking the spring-summer (28°C) and winter-autumn (22°C) mean values in Brazil. Detection of viral particles in the body, head and saliva samples was done by plaque assays in cell culture for determining the infection, dissemination and transmission rates, respectively. Compared with 28°C, at 22°C, transmission rates were significantly lower for both Ae. aegypti populations, and Ae. albopictus were not able to transmit the virus. Ae. albopictus showed low transmission rates even when challenged with the highest viral dose, while both Ae. aegypti populations presented higher of infection, dissemination and transmission rates than Ae. albopictus. Ae. aegypti showed higher transmission efficiency when taking virus doses of 105 and 106 PFU/mL following incubation at 28°C; both Ae. aegypti and Ae. albopictus were unable to transmit ZIKV with virus doses of 102 and 103 PFU/mL, regardless the incubation temperature. CONCLUSIONS/SIGNIFICANCE: The ingested viral dose and incubation temperature were significant predictors of the proportion of mosquito's biting becoming infectious. Ae. aegypti and Ae. albopictus have the ability to transmit ZIKV when incubated at 28°C. However Brazilian populations of Ae. aegypti exhibit a much higher transmission potential for ZIKV than Ae. albopictus regardless the combination of infection dose and incubation temperature.

Association Between Antenatal Exposure to Zika Virus and Anatomical and Neurodevelopmental Abnormalities in Children.

Importance: Zika virus (ZIKV) is a mosquito-borne flavivirus recognized as teratogenic since the 2015 to 2016 epidemic. Antenatal ZIKV exposure causes brain anomalies, yet the full spectrum has not been delineated. Objective: To characterize the clinical features of ZIKV infection at a pediatric referral center in Rio de Janeiro, Brazil, among children with antenatal ZIKV exposure. Design, Setting, and Participants: Retrospective cohort study conducted from May to July 2019 of a prospective cohort of 296 infants with antenatal ZIKV exposure followed up since December 2015 at a tertiary maternity-pediatric hospital. Exposures: Zika virus infection during pregnancy. Main Outcomes and Measures: Characterization of clinical features with anthropometric, neurologic, cardiologic, ophthalmologic, audiometric, and neuroimaging evaluations in infancy and neurodevelopmental assessments (Bayley Scales of Infant and Toddler Development, Third Edition) from 6 to 42 months of age, stratified by head circumference at birth (head circumference within the reference range, or normocephaly [NC] vs microcephaly [MC]). Results: Antenatal exposure to ZIKV was confirmed for 219 of 296 children (74.0%) referred to Instituto Fernandes Figueira with suspected ZIKV infection through positive maternal or neonatal polymerase chain reaction analysis or IgM serology results. Of these children, 110 (50.2%) were boys, ages ranged from 0 to 4 years, and 53 (24.2%) had congenital microcephaly. The anomalies observed in ZIKV-exposed children with MC or NC were failure to thrive (MC: 38 of 53 [71.7%]; NC: 73 of 143 [51.0%]), cardiac malformations (MC: 19 of 46 [41.3%]; NC: 20 of 100 [20.0%]), excess nuchal skin (MC: 16 of 22 [72.7%]; NC: 35 of 93 [37.6%]), auditory abnormalities (MC: 13 of 50 [26.0%]; NC: 14 of 141 [9.9%]), and eye abnormalities (MC: 42 of 53 [79.2%]; NC: 28 of 158 [17.7%]). Although they experienced fewer neurologic abnormalities than children born with MC, those with NC also had frequent neurologic abnormalities (109 of 160 [68.1%]), including hyperreflexia (36 of 136 [26.5%]), abnormal tone (53 of 137 [38.7%]), congenital neuromotor signs (39 of 93 [41.9%]), feeding difficulties (15 of 143 [10.5%]), and abnormal brain imaging results (44 of 150 [29.3%]). Among 112 children with NC with Bayley-III evaluations, 72 (64.3%) had average or above-average scores; 30 (26.8%) scored 1 SD below average in at least 1 domain; and 10 (8.9%) scored 2 SD below average in at least 1 domain. Among 112 children with NC, a smaller head circumference at birth was significantly associated with subsequent below-average cognitive scores (U = 499.5; z = -2.833; P = .004) and language scores (U = 235.5; z = -2.491; P = .01). Conclusions and Relevance: Children without MC who were exposed to ZIKV in utero had a high frequency of anatomical and neurodevelopmental abnormalities. The head circumference at birth for children with NC was associated with neurocognitive development. Recognition of the wide spectrum of clinical phenotypes is critical to ensure early referral to rehabilitative interventions.

Detection of coinfection with Chikungunya virus and Dengue virus serotype 2 in serum samples of patients in State of Tocantins, Brazil.

BACKGROUND: The co-circulation of Chikungunya (CHIKV), Dengue (DENV) and Zika (ZIKV) viruses increased the risk of outbreaks and coinfections among them. Here, we report cases of coinfection in clinical samples from state of Tocantins, Brazil. METHODS: In 2017, the Central Public Health Laboratory (LACEN) received samples of patients who consulted health units with symptoms compatible with arboviral infections. A total of 102 samples were sent to the Retrovirology Laboratory at the Federal University of São Paulo, where they were tested by RT-qPCR to confirm DENV, ZIKV and CHIKV infections and to detect coinfected patients. RESULTS: We identified with CHIKV monoinfection (52), DENV serotypes 1 (28) and serotypes 2 (22). We did not detect ZIKV. Five patients were characterized with coinfection involving CHIKV and DENV serotype 2. CONCLUSIONS: The presence of co-circulating arboviruses increases the chance of coinfection and demonstrates the importance of differential diagnosis and vector control.

Characteristics of Zika virus infection among international travelers: A prospective study from a Spanish referral unit.

BACKGROUND: From the first Zika virus (ZIKV) description, it has progressively widespread worldwide. We analyzed demographic, clinical, microbiologic and travel-related characteristic from returned patients from a ZIKV endemic country in a referral Tropical Medicine Unit. METHOD: A prospective cohort study performed in a Spanish referral center with the aim of determining the significant factors associated with confirmed Zika virus (ZIKV) infection. RESULTS: 817 patients, (56% women, median age 36 [IQR, Interquartile Range: 32-42]) were enrolled. Most had returned from Latin America (n = 486; 59.4%), travelled for tourism (n = 404; 49.4%) and stayed a median of 18 days (IQR: 10-30). 602 (73.6%) presented symptoms, but only 25 (4%) were finally diagnosed with confirmed ZIKV infection (including two pregnant women, without adverse fetal outcomes), 88% (n:22) presented with fever and 92% (n:23) with rash. 56% (n:14) arthralgia and/or myalgia and 28% (n:7) conjunctivitis. The presence of conjunctivitis, fever and rash were associated with an 8.9 (95% CI: 2.2-34.9), 6.4 (95% CI: 1.2-33.3) and 72.3 (95% CI: 9.2-563.5) times greater probability of confirmed ZIKV infection, respectively. CONCLUSION: Travel characteristics and clinical presentation may help clinicians to optimize requests for microbiological testing. Diagnosis of arboviriasis in travellers arriving form endemic areas remains a challenge for clinicians, but must be detected for the possible transmission outside endemic areas, where the vector is present.

Long-Term Protection of Rhesus Macaques from Zika Virus Reinfection.

By the end of the 2016 Zika virus (ZIKV) outbreak, it is estimated that there were up to 100 million infections in the Americas. In approximately one in seven infants born to mothers infected during pregnancy, ZIKV has been linked to microcephaly, developmental delays, or other congenital disorders collectively known as congenital Zika syndrome, as well as Guillain-Barré syndrome, in ZIKV-infected adults. It is a global health priority to develop a vaccine against ZIKV that elicits long-lasting immunity; however, the durability of immunity to ZIKV is unknown. Previous studies in mice and nonhuman primates have been crucial in vaccine development but have not defined the duration of immunity generated by ZIKV infection. In this study, we rechallenged five rhesus macaques with ZIKV 22 to 28 months after a primary ZIKV infection. We show that primary ZIKV infection generates high titers of neutralizing antibodies that protect from detectable plasma viremia following rechallenge and persist for at least 22 to 28 months. While additional longitudinal studies are necessary with longer time frames, this study establishes a new experimentally defined minimal length of protective ZIKV immunity.IMPORTANCE ZIKV emerged as a vector-borne pathogen capable of causing illness in infected adults and congenital birth defects in infants born to mothers infected during pregnancy. Despite the decrease in ZIKV cases since the 2015-2016 epidemic, questions concerning the prevalence and longevity of protective immunity have left vulnerable communities fearful that they may become the center of next ZIKV outbreak. Although preexisting herd immunity in regions of past outbreaks may dampen the potential for future outbreaks to occur, we currently do not know the longevity of protective immunity to ZIKV after a person becomes infected. Here, we establish a new experimentally defined minimal length of protective ZIKV immunity. We show that five rhesus macaques initially infected with ZIKV 22 to 28 months prior to rechallenge elicit a durable immune response that protected from detectable plasma viremia. This study establishes a new minimal length of protective immunity.

Variations in maternal adenylate cyclase genes are associated with congenital Zika syndrome in a cohort from Northeast, Brazil.

BACKGROUND: Vertical transmission of Zika virus (ZIKV) is associated with congenital malformations but the mechanism of pathogenesis remains unclear. Although host genetics appear to play a role, no genetic association study has yet been performed to evaluate this question. In order to investigate if maternal genetic variation is associated with Congenital Zika Syndrome (CZS), we conducted a case-control study in a cohort of Brazilian women infected with ZIKV during pregnancy. METHODS: A total of 100 women who reported symptoms of zika during pregnancy were enrolled and tested for ZIKV. Among 52 women positive for ZIKV infection, 28 were classified as cases and 24 as controls based on the presence or absence of CZS in their infants. Variations in the coding region of 205 candidate genes involved in cAMP signaling or immune response were assessed by high throughput sequencing and tested for association with development of CZS. RESULTS: From the 817 single nucleotide variations (SNVs) included in association analyses, 22 SNVs in 17 genes were associated with CZS under an additive model (alpha = 0.05). Variations c.319T>C (rs11676272) and c.1297G>A, located at ADCY3 and ADCY7 genes showed the most prominent effect. The association of ADCY3 and ADCY7 genes was confirmed using a Sequence Kernel Association Test to assess the joint effect of common and rare variations, and results were statistically significant after adjustment for multiple comparisons (P < 0.002). CONCLUSION: These results suggest that maternal ADCY genes contribute to ZIKV pathogenicity and influence the outcome of CZS, being promising candidates for further replication studies and functional analysis.

Zika Virus Infection Among Pregnant Women and Their Neonates in New York City, January 2016-June 2017.

OBJECTIVE: To describe and compare differences in the epidemiologic, clinical, and laboratory characteristics of pregnant women with confirmed or probable Zika virus infection and to compare the risk of having a neonate with laboratory evidence of Zika virus infection with that of having a neonate without evidence of Zika virus infection by maternal characteristics. METHODS: We conducted a retrospective cohort study of women with Zika virus infection who completed pregnancy in New York City from January 1, 2016 to June 30, 2017. Confirmed Zika virus infection was defined as 1) nucleic acid amplification test-detected Zika virus, or 2) a nonnegative enzyme-linked immunosorbent assay test result and a plaque-reduction neutralization test result positive for Zika virus but negative for dengue virus, or 3) delivery of a neonate with laboratory evidence of Zika virus infection. Probable infection was defined as a nonnegative enzyme-linked immunosorbent assay test result and a positive plaque-reduction neutralization test result for Zika virus and dengue virus. RESULTS: We identified 390 women with confirmed (28%) or probable (72%) Zika virus infection. Fever, rash, arthralgia, or conjunctivitis was reported by 31% of women and were more common among women with confirmed than with probable infection (43% vs 26%, P=.001). Of 366 neonates born to these women, 295 (81%) were tested for Zika virus and 22 (7%) had laboratory-diagnosed congenital Zika virus infection. The relative risk (RR) for having a neonate with laboratory evidence of Zika virus infection was greater among women with fever (RR 4.8, 95% CI 2.1-10.7), tingling (RR 4.8, CI 1.7-13.7), or numbness (RR 6.9, CI 2.6-18.2) during pregnancy or the periconception period. However, the RR did not differ whether the mother had confirmed or probable Zika virus infection (RR 1.6, CI 0.7-4.1). CONCLUSION: In New York City, a greater proportion of women had probable Zika virus infection than confirmed infection. Women with some symptoms during pregnancy or periconceptionally were more likely to have a neonate with laboratory evidence of Zika virus infection. Neonates born to women with confirmed or probable Zika virus infection should be tested for Zika virus infection.

Acciones que realiza el hombre para prevenir el embarazo ante el virus del Zika / Action that man performs to prevent pregnancy against the Zika virus

Según la Organización Mundial de la Salud (OMS), el virus del Zika es "un flavivirus transmitido por mosquitos que se identificó por vez primera en Macacos, Uganda 1947 a través de una red de monitoreo de la fiebre amarilla". Objetivo: Identificar el conoci-miento y acciones que realizan los emplea-dos masculinos de mantenimiento de la Uni-versidad Nacional Autónoma de Honduras en el Valle de Sula (UNAH-VS) para la prevención del embarazo ante el virus del Zika, durante el segundo semestre del año 2016. Pacientes y métodos Estudio cuanti-tativo exploratorio, descriptivo. Población 29 hombres, muestra 28. Instrumento tipo cuestionario, previo consentimiento informa-do. Resultados: El 61% (17) tenían edad reproductiva (20-35 años), 96% (27) esta-ban activos sexualmente, 14% (4) sí tenían conocimiento que el virus del Zika permane-ce en el semen del hombre. El 89% (25) sí conocia que el virus del Zika en el embarazo causa microcefalia en el bebé por nacer, 11% (3) no, 21% (6) sí utiliza algún método para prevenir el embarazo con su pareja, 79% (22) no utilizan métodos anticoncepti-vos y 83% (23) no saben cuanto tiempo abs-tenerse sin protección en las relaciones sexuales. Conclusión: Los resultados señalan que el personal masculino de man-tenimiento de la UNAH-VS, la mayoría des-conoce que el virus permanece en el semen Artículos Originalesdel hombre despues de la patología; por lo tanto no toman medidas preventivas ante un posible embarazo...(AU)