Europe’s ability to respond effectively to health threats has already been called into question by the coronavirus pandemic. Heroic collaboration between researchers and policymakers has made the first vaccines available at record speed, but Europe still stands before a major challenge that goes way beyond the current COVID crisis. There is a critical failure to develop and implement the testing technologies that not only can help protect citizens against COVID-19, but that will also be crucial in preserving public health over the longer term, in the face of future and even more deadly cross-border infections, writes European Alliance for Personalised Medicine (EAPM) Executive Director Dr. Denis Horgan.

To address these topics, EAPM hosted two webinars on the matter. The first virtual round table, ‘Forward together with innovation: Understanding the need and framing the discussion for Serology testing for SARS-CoV‘, took place on 17 December 2020, and the on ‘Recruiting serology to the long fight ahead against pandemics‘, on 3 February. Together they comprehensively highlighted the questions still needing answers and gathered input from European and international public health officials and organisations, academia, and industry.

As the experts concluded, action is needed to introduce meaningful testing strategies leveraging the comprehending strengths of the available testing technologies such as serology. This can contribute to more efficiency of vaccination programs.

Not the end of a battle – just the beginning

“We are only at the beginning now,” Bettina Borisch, Executive Director World Federation of Public Health Associations, told a recent expert roundtable on serology testing, organised by EAPM to highlight the challenges and opportunities of making the best use of testing. “We are confronted with not just a short-term crisis but a long one, to ensure future capacity for protection.” Testing and diagnosis have been Cinderella areas of medicine for too long, she said, urging the use of serology as a vital element in any pandemic strategy. The point was reaffirmed by Kevin Latinis, a scientific advisor for one of the US task forces to tackle Covid, at a follow-up EAPM roundtable in January: “The pandemic has demonstrated dramatically what an asset adequate testing would be, but the opportunity is being missed,” he said. Or, as Denis Horgan, EAPM’s executive director, who chaired both roundtables, expressed it: “More vaccines are now becoming available, but it is vital to ensure they are used effectively in clinical practice, and for that we need better understanding of which patients will respond to different vaccines and how the vaccines will tackle variants.”

The confident but chilling scientific consensus is that the next decades will bring further and more virulent pandemics that threaten disruption and death on an even greater scale than the current outbreak. And while the hope is that vaccines now being created in extremis will overcome the immediate danger, Europe – and the world – can no longer afford to rely on hasty improvisation. The harsh reality is that much of the current vaccine development is shooting in the dark at moving targets.

As the first vaccines reach the general public at the start of 2021, it is still unknown for how long vaccination confers immunity (and, topically, how much flexibility in altering dosage schedules is justified), how it affects different population groups, or to what extent vaccination impedes transmission. As the European Medicines Agency observes in reporting on its first positive opinion on a Covid vaccine, Comirnaty, “It is not currently known how long protection given by Comirnaty lasts. The people vaccinated in the clinical trial will continue to be followed for two years to gather more information on the duration of protection.” And “there were not enough data from the trial to conclude on how well Comirnaty works for people who have already had COVID-19.” Similarly, “The impact of vaccination with Comirnaty on the spread of the SARS-CoV-2 virus in the community is not yet known. It is not yet known how much vaccinated people may still be able to carry and spread the virus.”

Sharper identification of the nature of the virus – and any of its mutated variants – as well as greater precision over the effectiveness of vaccines and measurements of immunity are still urgently needed.

Help is at hand – in principle…

The mechanisms are available to bring that precision and clarification. Notably, serology testing can help confirm the efficacy of vaccination, and could be used to establish a threshold for protection or immunity. It can also confirm an initial antibody response from vaccination, and provide subsequent tracking of antibody levels at regular intervals. Because data from initial vaccine trials will be limited to certain populations and exposure patterns, serology can provide additional data on antibody response and duration to help inform vaccine efficacy in larger, more-diverse populations, and to determine appropriate use in the context of variables such as ethnicity, level of viral load exposure, and individual immune system strength. Testing is vital also to distinguish successful from suboptimal vaccine responses and to detect antibody declines after natural infection.

How serology testing works

Serology is the study of antibodies in blood serum. Serologic antibody tests help determine whether the individual being tested was previously infected, by measuring the person’s immune response to the virus—even if that person never showed symptoms. Antibodies are immune proteins that mark the evolution of the host immune response to infection, and they provide an archive that reflects recent or previous infection. If maintained at sufficiently high levels, antibodies can rapidly block infection on reexposure, conferring long-lived protection.

Serology tests are not the primary tool for diagnosing an active infection, but they provide information essential to policymakers. They help determine the proportion of a population previously infected with SARS-CoV-2, providing critical information on infection rates at a population level, and providing information about populations that may be immune and potentially protected. Accurate assessment of antibodies during a pandemic can provide important population-based data on pathogen exposure, facilitate an understanding of the role of antibodies in protective immunity, and guide vaccine development. Population-level surveillance is also critical to the safe reopening of cities and schools.

..but not always in practice

Serology testing is not being used systematically, and in many EU countries there is still hesitation over putting in place the organisation and infrastructure to make it possible.

The European Commission has already pointed out that short-term EU health preparedness depends on robust testing strategies and sufficient testing capacities, to permit early detection of potentially infectious individuals and to provide visibility on infection rates and transmission within communities. Health authorities must also equip themselves to conduct adequate contact tracing and run comprehensive testing to rapidly detect an increase in cases and to identify groups at high risk of disease, it has said in its guidance. But at present, European countries are in many cases falling short and functioning sub-optimally.

Charles Price of the European Commission’s health department, DG Santé, admitted that despite the recent intensive collaboration among European Union institutions and the member states, “We are still short of consensus on the best serology tests for particular jobs – to assess the level of infection, to inform vaccination strategies, or to inform clinical decision-making on individuals.” These all depend on good serology testing, and the EU is trying to coordinate additional observation at country level of vaccinated populations to feed into evaluation of vaccines by the European Medicines Agency, he told the round table.

Hans-Peter Dauben, secretary general of Euroscan, the international health technology assessment network, also admitted that authorities are often too slow: “We don’t have a model to improve our understanding of what is going on,” he said. Serological data can be collected within existing systems, he said, but there is no consensus on how it can be used.

He pointed out that while there are multiple settings and scenarios where a diagnostic technology can be used, ranging from clinical usage on treatment decisions in outpatient and inpatient care, and in public health interventions on isolation, tracing and tracking, and epidemiology, “Each scenario requires a unique approach with a set of validation criteria located in the relevant decision-making context.”

Exploring the questions

Given the current uneven degree of readiness and capacity among European countries to utilize serology testing technology, and the current absence of plans for systematic serological testing for surveillance, Horgan queried how far public health professionals and institutes understand the barriers and enablers to adoption of serology testing in vaccination surveillance systems. And he questioned whether revised recommendations were needed from the EU on testing strategies and on adaptations to different types of vaccines. “We need to know who to vaccinate and how to vaccinate, and we need to allocate resources accordingly,” he said.

Achim Stangl, Medical Director at Siemens Healthineers, was concerned that there is insufficient information about what subpopulations particularly benefit from vaccination, such as immunosuppressed patients, lymphoma patients, or very young children. His colleague Jean-Charles Clouet insisted that there are still open questions on vaccines that only testing will elucidate: “The importance has not been fully grasped of showing the impact of vaccination on the immune system, and of conducting long-term monitoring to define an optimal immunity threshold.” Latinis focused on the need to understand not only the immunity conferred by vaccines, but also how far and fast it wanes. Or as Stangl put it, “The big question is how long antibodies are present and able to provide immunity

The questions come in the wake of many similar expressions of concern and counsel. The International Coalition of Medicines Regulatory Authorities warned in 2020 of the need for “stringent regulatory requirements for Covid-19 studies” and agreed to provide guidance on the prioritisation of clinical trials and on serology in order to promote a harmonised approach. The US Centre for Disease Control has issued serology testing guidelines listing important applications in monitoring and responding to the COVID-19 pandemic.

The World Health Organisation states clearly that the use of serology in epidemiology and public health research enables understanding of the occurrence of infection among different populations, and how many people have mild or asymptomatic infection, and who may not have been identified by routine disease surveillance. It also provides information on the proportion of fatal infections among those infected, and the proportion of the population who may be protected against infection in the future. Information that might impact serologic recommendations is rapidly evolving, particularly evidence of whether positive serologic tests indicate protective immunity or decreased transmissibility among those recently ill.

What can be done?

Serology is the scientific study of serum and other body fluids. In practice, the term usually refers to the diagnostic identification of antibodies in the serum.[1] Such antibodies are typically formed in response to an infection (against a given microorganism),[2] against other foreign proteins (in response, for example, to a mismatched blood transfusion), or to one’s own proteins (in instances of autoimmune disease). In either case, the procedure is simple.

Serological tests are diagnostic methods that are used to identify antibodies and antigens in a patient’s sample. Serological tests may be performed to diagnose infections and autoimmune illnesses, to check if a person has immunity to certain diseases, and in many other situations, such as determining an individual’s blood type. Serological tests may also be used in forensic serology to investigate crime scene evidence. Several methods can be used to detect antibodies and antigens, including ELISA,[4] agglutination, precipitation, complement-fixation, and fluorescent antibodies and more recently chemiluminescence.

All this increases the chances of monitoring the spread of Covid-19 infection. Vicki Indenbaum of the World Health Organization told the round table that serology will become more important not only before vaccination, but after vaccination takes place, to let public health decision-makers know exactly what is going on, and what proportion of population has been infected. It is, she said, an essential element to ensure trust between policymakers, professionals and the public. Sarper Diler, a Faculty Member Istanbul University Istanbul Medical Faculty in Turkey, similarly urged a more rigorous schedule of serology tests, “before vaccination, and some months after to see whether a booster shot is needed or not, and to see the impact on wider populations.” He also called for development of wider array testing to detect antibodies as vaccines – and virus variants – evolve.

What’s needed now

A co-ordinated response across Europe – and beyond – is needed now to ensure that serology can play its part in defending citizens against pandemic infections.

Diler emphasised the importance of communication with citizens to minimize fear and anxiety and non-compliance with preventive behaviour: “We have to find a common language to communicate, and right now it is lacking in Europe,” he said. His point was reinforced by Latinis and Daubens, who both warned that a confusion of voices is distracting for strategy formation and implementation. Boccia too urged building trust among public and professionals so as to minimise the likelihood of vaccine hesitancy – and for this, she indicated, clarity over the mechanisms of vaccination is essential.

Some consensus emerged from the roundtables on the need for testing itself to be refined and stepped up. Serology assays should have the appropriate characteristics for assessment of need to vaccinate and vaccine response: an automated, scalable serology assay used in the context of vaccination should include key technical features for effective use: measurement of spike receptor-binding domain neutralizing IgG antibodies, very high (≥99.5%) specificity, and quantitative results.

The requirements also extend to infrastructure. This applies to capacity as well as to physical facilities. Availability at a large and accessible scale is key to ensuring that the needs of the population can be met. This would allow for measuring antibodies in relation to vaccine use for establishing a threshold for protection or immunity, for confirming an initial neutralizing antibody response shortly (approximately 1 week to 1 month) after vaccination, and for tracking of antibody levels (at approximately 3, 6, and 9 months and annually) following vaccination. In the event of limited vaccine availability, antibody assessment can also support decision making for administration to the most vulnerable populations.

Strangl pointed out that the unprecedented speed at which COVID 19 vaccines have been developed leaves the scientific community with very limited data on duration of effective immunity and safety, and on the variability of responses among minority and underserved populations, children and the elderly, “many of whom may not develop antibodies to one or another of the vaccines,” he added.

In these circumstances, serology testing can prioritize the use of vaccine resources and inform long-term vaccination strategy. Prior to vaccination, it can help prioritize individuals for vaccination , establish serological baselines and help ensure scarce supply reaches the most vulnerable. Testing one week to one month after vaccination can confirm an initial neutralizing antibody response, and help ensure that the antibody response clears the threshold for immunity. Further testing 3 six and nine months after vaccination can confirm persistence and duration of immunity , and can provide the means 2 agree on abridged trial requirements for additional populations. And testing annually after vaccination can assess persistence and duration of immunity and inform requirements for future vaccinations.

As Stangl summarized it: “Successful implementation of broad serological testing will require the right tools.” This means quantitive considerations to establish a protective threshold, assess response and monitor antibody levels overtime. It means testing of specificity high enough for investigating responses in low-prevalence populations, and capable of minimizing false positive results. And it means capacity, reach and speed for sufficient production to address large populations, a large fleets of immunoassay analyzers installed worldwide, and high analyzer productivity and ease of use.

The European Commission’s Communication ‘Preparedness for COVID-19 vaccination strategies and vaccine deployment’ notes that “to monitor the performance of the vaccination strategies, it is essential for member states to have suitable registries in place. This will ensure that vaccination data is appropriately collected and enables the subsequent post-marketing surveillance and ‘real time’ monitoring activities. Member states should ensure that …vaccination registries are up-to-date”. Dauben suggested that all vaccinated patients should be included on a mandatory registry to allow proper study of the effects.

Stefania Boccia of Milan’s Università Cattolica del Sacro Cuore quoted the recommendations of the EU expert panel on effective ways of investing in health, including integrating information and communication technologies across care levels and public health, and investment in comprehensive resilience testing of health systems and sharing of lessons. She also highlighted findings from EU surveys of member states over recent months that show the still incomplete status of monitoring systems for vaccine coverage, safety, effectiveness and acceptance. Survey conclusions also note that recommendations will be updated “as more evidence becomes available about COVID-19 disease epidemiology and characteristics of vaccines, including information on vaccine safety and efficacy by age and target group.”

A serology-defined threshold (from either natural infection or vaccination) remains a key need, and this periodic testing would offer additional data on antibody response patterns to determine optimal serology testing utilization. Longer-timeframe quantitative testing for waning levels of protective antibody, such as through annual testing, would inform the need to revaccinate/boost.

To bring these changes into play, policymakers will need evidence, along with data points needed to substantiate that evidence. A framework of panels of experts will have to be created in which guidance can be offered to support decisions on the use of serological testing. And as Latinis remarked, “It is ultimately up to us who uses serology testing to convince politicians to implement it.”

And where should this go?

The round table concluded that this was a key moment for the development of a new approach to pandemic preparedness. The current spread of infection – lamentable though it is in its human consequences – provides an unprecedented scientific opportunity for improving understanding of immunity, vaccination and related mechanisms. With adequate, and adequately rigorous, testing in place, it will be possible to evaluate without risk of bias different populations being treated with different vaccines across the world.

To allow the benefits to accrue from this situation, data will have to be collected and compared from a wide range of studies, and at a truly global scale. This in turn will depend on all stakeholders being ready to operate outside and across the customary siloes that characterise the health community, and to adopt a common language based on a new literacy. But by extension of the EU’s new ambition to build a European health union, and taking as a model such international concords as the Paris climate agreement or the UN framework convention on tobacco control, what could and should emerge is a co-ordinated international response to future health crises of this scale, in an international pandemic treaty.

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