Featured Journal Content – Dengue Vaccine
In this month’s issue, Kevin Ariën and Annelies Wilder-Smith outline the ideal attributes of a diagnostic test to identify previous exposure to dengue virus. The need for such an assay stems from the worrying revelation by Sanofi Pasteur last November that its licensed tetravalent vaccine, Dengvaxia, was associated with an increased risk of severe dengue in individuals who were seronegative for dengue virus at the time of vaccination. It was assumed that the vaccine, the efficacy of which is higher for serotypes 3 and 4 than for 1 and 2, was mimicking a primary infection, which is known to be a risk factor for future severe disease if the individual becomes infected with a different serotype at a later date. Sanofi Pasteur thus proposed a label change to the effect that vaccination should not be recommended in those who have not been previously infected. Further, in April, 2018, WHO’s Strategic Advisory Group of Experts on Immunization (SAGE) released revised recommendations that also indicated a preferred strategy of prevaccination screening for previous exposure and vaccination only of seropositive individuals. SAGE additionally called for research into “development of a highly sensitive and specific rapid diagnostic test to determine serostatus”.
In the Philippines—where the disease is highly prevalent and whose Government boldly announced a programme to vaccinate 830,000 schoolchildren in 2016—this transparent, cautious, and responsible approach to a safety concern was unfortunately lost amid an avalanche of alarmist governmental statements, screaming headlines, and law suits. The Government withdrew approval of the vaccine in December 2017.
What can cause a public health programme to go so disastrously wrong and what can academics, health professionals, and communicators do to assuage concerns about vaccine safety? These were some of the questions put to a panel of experts at the International Society for Neglected Tropical Diseases 3 in London last month. Tikki Pangestu, professor at the Lee Kuan Yew School of Public Policy in Singapore and previously of WHO, highlighted what he saw as the “enabling environment” that led to the dengue vaccine saga. First, the immunisation programme was launched in the Philippines to much fanfare very swiftly after the vaccine’s approval and during an election year. The Government’s eagerness to introduce the programme could thus have been seen as politically motivated. Second, a failure of leadership saw public health officials join with anti-vaccine groups and a media focused on getting a juicy story to seed mass fear among parents. Finally, and common to all immunisation programmes, is the very concept of intervening medically in healthy children—an understandably combustible notion, the benefits, risks, and uncertainties of which are difficult to convey to a lay audience. Add to these general elements of distrust the tensions between individual rights and wider societal benefits, and religious and philosophical beliefs, and you have quite an explosive mix, added Pauline Paterson from the London School of Hygiene and Tropical Medicine’s Vaccine Confidence Project.
The answer? “Very difficult”, said Paterson. Psychological research shows that changing misconceptions is not easy, and that the mere process of debunking a myth can make the myth more prominent in the mind of the receiver. However, identifying susceptible populations, exploring the underlying reasons for non-vaccination, and designing evidence-informed responses are important features of success, she advised. Additionally, people are more likely to vaccinate or be vaccinated if a health-care provider recommends it, and vaccinated health-care providers are more likely to recommend vaccination to others. Some clear messages to health-care providers, then: acknowledge your patients’ concerns, engage with them, recommend vaccination, and get yourself or your children vaccinated.
And what about communicators? We are all communicators, insisted Sanofi Pasteur’s Angus Thomson. Researchers, practitioners, editors, and policy makers can and should be part of the discussion, he said, offering evidence to counter misinformation where we encounter it on social media, helping journalists to understand complex risk-benefit scenarios, and assisting governments with risk management planning. “Don’t wait for the crisis before you lean into the problem”, agreed Rachel Grant from the Coalition for Epidemic Preparedness Innovations (CEPI).
Finally, we need to be prepared to meet individuals wherever their own personal beliefs lie and not simply try to convert them to our own mindset. Because one thing we cannot assume in this “me first” era is that every citizen will see the wider societal benefits as a good reason to take a personal risk, however small that may be in reality.
Dengue vaccine: reliably determining previous exposure
Kevin K Ariën, Annelies Wilder-Smith
Dengue fever is the most prevalent and widespread mosquito-borne viral disease, and can only be countered by integrated prevention and control strategies, including sustained vector control programmes, the best evidence-based clinical care, and vaccination.
The first dengue vaccine, CYD-tetravalent dengue vaccine (CYD-TDV) or Dengvaxia (Sanofi Pasteur, Lyon, France), is licensed in 20 countries. Initial findings from two large phase 3 clinical trials have shown good but incomplete protection, in particular against severe dengue and dengue disease that requires hospital admission.1, 2 In November, 2017, Sanofi Pasteur announced the results from additional studies showing that the vaccine has a differential performance in individuals who have previously been infected by dengue virus (seropositive) versus those without previous dengue virus infection (seronegative).3 Vaccine efficacy against laboratory-confirmed symptomatic dengue virus infection was high among individuals who were seropositive at baseline and aged at least 9 years (76%, 95% CI 63·9–84·0), but much lower among participants who were seronegative at baseline (38%, −0·9 to 62·9). Furthermore, vaccination of individuals who are seronegative increases their risk of severe dengue or dengue that requires hospital admission.4 Subsequently, in April, 2018, WHO’s Strategic Advisory Group of Experts recommended that in countries considering the introduction of vaccination with CYD-TDV, pre-vaccination screening should be preferred to assess dengue virus serostatus, and only people who are dengue seropositive should be vaccinated. To this end, WHO also encouraged the urgent development of rapid diagnostic tests (RDTs) to establish serostatus.
Because dengue viruses are of the genus Flavivirus, composed of genetically, structurally, and antigenically related viruses, such as Zika virus, yellow fever virus, and tick-borne encephalitis virus, antibody detection tests have high cross-reactivity and consequently poor reliability for the diagnosis of past dengue virus infection.5 With large flavivirus-exposed populations in Latin America, Asia, and Africa, a rapidly growing population of travellers from and to endemic areas,6 and increased vaccination coverage against yellow fever virus, tick-borne encephalitis virus, and Japanese encephalitis virus in travellers and in certain endemic regions, it is evident that establishing serostatus is extremely challenging.
Many commercial immunoglobulin (Ig)G-containing point-of-care tests (POCTs) and dengue IgG ELISA assays are available. For the purpose of pre-vaccination screening, the assay with the highest sensitivity and specificity would be the desirable option. Low sensitivity would result in under-vaccinating individuals who are truly seropositive and who would benefit from the vaccine, whereas low specificity would lead to falsely vaccinating people who are truly seronegative, putting them at risk of severe dengue during the next natural infection with dengue virus.
The plaque reduction neutralisation test (PRNT) is still considered the gold standard for establishing serostatus, but requires specific laboratory and technical capacity, and is labour intensive, costly, and time consuming. Although dengue IgG ELISA correlates reasonably well with the results of a PRNT, the test has a lower sensitivity and specificity than PRNT, although the studies7, 8 that showed this lower sensitivity and specificity were done before Zika virus became a widespread problem in the Americas. Dengue IgG ELISA requires about 2·5 h of laboratory time, excluding the time needed for sample transportation to the laboratory, batch analysis, and reporting to the clinician, which requires two visits for the vaccinees. Point-of-care testing that uses RDTs provides the vaccine recipient with a result within 15–30 min, and can be done in an outpatient or outreach setting, such as schools and care facilities, using a finger prick sample. Thus, a decision on vaccination eligibility can be made during the same visit, thereby ensuring a reasonable vaccine uptake. POCTs generally have lower sensitivity and specificity than dengue IgG ELISAs. However, this low sensitivity and specificity needs to be weighed up against the faster speed of testing, lower cost, and improved accessibility outside specialised laboratories compared with IgG ELISAs.
As available RDTs were mainly developed for the purpose of diagnosing acute dengue virus infection, further efforts would be justified to fine-tune such RDTs to increase sensitivity and specificity for diagnosing serostatus. To increase the sensitivity of dengue RDTs to detect previous dengue virus infection, several modifications could be contemplated, one of which would be recalibration by changing the concentration of the IgG capture antigen or detection reagent to lower the limit of anti-dengue IgG detection. To address cross-reactivity with other flaviviruses, particularly Zika, other modifications should be considered to improve specificity.
Diagnostic methods for flavivirus antibody detection use the entire virus particle, recombinant surface E-protein, or NS1 protein as antibody-capturing antigens. Epitopes with high aminoacid sequence homology among serotypes or flaviviruses can trigger cross-reactive responses, but type-specific antibodies directed towards unique E and NS1 epitopes are also raised.9, 11 The art of making specific serological tests lies in the identification, selection, and presentation of those epitopes, either as recombinant protein fragments or peptides that only bind type-specific IgG, instead of using the entire virion or recombinant protein that contains both type-specific and cross-reactive antibody epitopes. Dengue virus antibody tests that use recombinant E-protein to absorb IgG will not be useful anymore for pre-testing purposes or for seroprevalence studies once the dengue vaccine (that uses dengue virus E-protein as an immunogen) is widely spread. Capturing type-specific non-E-protein-directed antibodies could be an alternative approach, as applied in the recently developed Zika virus-specific NS1 blockade-of-binding ELISA.10 Comparative epitope modelling and genome-wide peptide microarray analysis can help to identify virus-specific epitopes targeted by antibodies in individuals who are flavivirus seropositive. Whereas obtaining type-specific epitopes is challenging but technically feasible, the difficulty might be in retaining sufficiently high sensitivity when aiming to detect specific subsets of antibodies in people who have been exposed to flavivirus. The epitope specificity and the abundance of such subsets of antibodies might also differ between populations and individuals as a result of differences in genetic background, co-circulating pathogens, vaccination, history of natural infection, and timing of sampling. Combining multiple type-specific epitopes and antigen–antibody crosslinking could potentially help address this issue. Evaluation platforms and access to well characterised samples to accelerate test development and access to market are urgently needed.
We declare no competing interests. KKA serves as a consultant on diagnostics to WHO and AW-S as a consultant on arboviral diseases to WHO. KKA also serves as an expert for the Belgian Federal Agency for Medicines and Health Products. The views expressed in this manuscript do not necessarily represent the views of WHO or the Belgian Federal Agency for Medicines and Health Products. KKA is a member of ZikaPLAN and AWS is the coordinator of the ZikaPLAN consortium that received funding from the European Union’s Horizon 2020 research and innovation programme, under the ZikaPLAN grant agreement 734584.4.
References at title link above
Countries step up to tackle antimicrobial resistance
Joint News Release – FAO-OIE-WHO
18 July 2018
Countries are making significant steps in tackling antimicrobial resistance (AMR), but serious gaps remain and require urgent action, according to a report released today by the Food and Agriculture Organization of the United Nations (FAO), World Organisation for Animal Health (OIE) and the World Health Organization (WHO).
The report charts progress in 154 countries and reveals wide discrepancies. Some, including many European countries, have been working on AMR policies in human and animal sectors for more than 4 decades. Others have only recently started to take action to contain this growing threat. Progress in developing and implementing plans is greater in high-income than low-income countries but all countries have scope for improvement. No country reports sustained capacity at scale in all areas.
The report looks at surveillance, education, monitoring and regulating consumption and use of antimicrobials in human health, animal health and production, as well as plants and the environment – as recommended in the Global Action Plan published in 2015.
Promising findings include 105 countries with a surveillance system in place for reporting drug-resistant infections in human health and 68 countries with a system for tracking consumption of antimicrobials. In addition, 123 countries reported that they have policies to regulate the sale of antimicrobials, including the requirement of a prescription for human use – a key measure to tackle overuse and misuse of antimicrobials.
But implementation of these policies varies and unregulated medicines are still available in places such as street markets, with no limits on how they are used. Medicines are very often sold over the counter and no prescription is requested. This puts human and animal health at risk, potentially contributing to the development of antimicrobial resistance…
Link to database and report: http://www.who.int/antimicrobial-resistance/global-action-plan/database/en/