Recommendation of the Hungarian Academy of Science on the management of the COVID-19 epidemic in the short and long term

The Presidential Committee for Health of the Hungarian Academy of Sciences (EBE) was established in 2017. Its latest statement has provided a comprehensive overview of the 21^st century health care system under the title “Prerequisites for health care in our age”. The committee has, however, been established with the intention to mobilise its wide range of expertise to address the more specific issues of today’s overwhelmingly complex health system as well. Its main task is to review scientific evidence, to inform the decision-makers, the government and the public.

The management of the COVID-19 pandemic has emerged as an exclusive priority overriding any other issue on this year’s agenda of the committee. An ad-hoc group was formed including outstanding immunologists, medical doctors and biologists who all volunteered to take advantage of several on-line brainstorming sessions and prepare a recommendation that is informed by leading scientific papers, reports and publications of respectable learned societies, and the expert knowledge of group members. The recommendation aims to call the attention of decision-makers to the major issues that need to be addressed urgently in order the manage the post-peak period of the pandemic with success.

The recommendation was prepared by András Falus, Gábor Makara, Ferenc Oberfrank, Balázs Sarkadi, András Váradi and Zoltán Vokó and was finalised and approved both by the Presidential Committee for Health and the Medical Section of the Hungarian Academy of Sciences counting 15 and 30 members respectively. The recommendation was published on the website of the Academy and sent directly to the Minister of Interior, the Minister of Human Capacities, the Minister for Technology and Innovation and the Chief Medical Officer as the leader of the National Public Health Center.

We would like to take this opportunity to emphasize the readiness of the Hungarian Academy of Sciences to prepare further editions of recommendations, to organise or to take part in interdisciplinary research and to support the application of scientific results in any possible way in the fight against the virus.

Budapest, 22 April, 2020

László Lovász, president of the Hungarian Academy of Sciences

György Kosztolányi, president of the EBE

Recommendations for decision-makers

Executive summary

This report prepared by the Presidential Committee for Health of the Hungarian Academy of Sciences provides an overview of the key areas of epidemiological control, among them considerations for crisis management, the medical (diagnostic and therapeutic) aspects and the scientific facts behind the pandemic. It lists the main areas of professional advice and makes recommendations for the government and the national authorities on the management of the COVID-19 pandemic in the short and long run.

Key recommendations:

• We need scientifically approved data about the COVID-19 pandemic, which shall be collected based on systematic, validated and accredited testing.
• Targeted epidemiological measures both in the short and the long run must be taken to identify and register groups of individuals who are susceptible or immune to COVID-19 disease.
• On the basis of experience, considerably strengthened institutional and educational foundations for public health must be created urgently, communication of public information and communication among and within expert groups must be improved.
• Once COVID-19 vaccines become available, we need to prepare for the creation of target groups based on different levels of individual protection.
• To mitigate the effects of a potentially long-term COVID-19 pandemic or any other currently unknown outbreak, we need to strengthen scientific research in all affected areas.
• Regarding the future, we need to assess the indirect impact of the pandemic on patients with any chronic disease, and prepare for the serious consequences that are likely to emerge as a result of missed screenings and delayed or cancelled medical examinations and treatments. The already overburdened and underfinanced healthcare system is expected to face even longer waiting lists and delayed diagnoses in the future.

In the current phase of the COVID-19 pandemic, characterised by an increasing rate of infection, government measures have mostly taken place already. However, the adjustment and the selective and targeted application of these measures is still recommended. Already at this stage, it is necessary to consider preparatory measures for the post-peak period and future pandemics.

The first wave of the COVID-19 pandemic may prove to be significantly prolonged and it is likely that future waves will follow. This requires timely and adequate measures to manage or prevent.

An overview of the current situation and possible future scenarios

A. Initial hypotheses

1. Infected individuals, who are carriers of the virus, are to be treated as major sources of risk.
   
   
2. Susceptible and immune persons must be identified and registered using targeted tests which are validated according to common international standards.
   Based on our current knowledge, the first wave of the pandemic is likely to leave a major part of the population susceptible to the infection, but there will be a high number of people who will have developed immunity, for at least a couple of months, perhaps years, to SARS-CoV-2.
   
   
3. The protection of the most vulnerable groups must be sustained.
   If we succeed in protecting the most vulnerable groups during the first wave of the epidemic, only a few among them will be contracted by the virus, so the protection of these groups will need to be maintained for a longer period.

4. Epidemic quarantine measures are to have a long, but finite duration.
   
   
5. Extensive protection measures must be in place until a majority of the population develops immunity either through infection or vaccination.
   
   
6. Selective, targeted and evidence-based actions of epidemic control (based both on infection and immunisation data measurements) are more cost-effective than general measures based on give and take improvisation.

B. The scope of action and tasks of epidemic control in the short and long run

In order to ensure an appropriate planning of epidemic control measures, we need to have reliable estimates including regional infection data of the population of the entire country. Once these data are available, differentiated measures and an array of selective protective actions can be employed to minimize damage to public health and the economy.

1. In the short term, in the first phase of epidemic control, measures enforced by public authorities are inevitable. While physical distancing may indeed be an effective tool in combatting the spread of the disease during the initial wave of infections, the general application of social distancing for an indefinite period of time is likely to be increasingly difficult to enforce. Such measures are set to be compromised by the growing economic loss and the deterioration of the mental health of people as a result of being locked-up and isolated.
   
   The method of relaxing restrictions in a comprehensive and recurring manner is not recommended without appropriate testing and modelling calculations. That is because any increase in new infections as a result of such easing will only become apparent after a fairly long incubation period, with a delay of 2 or most probably even 3 to 4 weeks. These cases will only appear in medical records in another 2-3 weeks, thereby making any timely adjustment to such actions considerably harder.
   
   To ensure the efficacy of short-term measures of public authorities, it is essential to have validated tests on the prevalence of the virus in patients by real-time PCR molecular diagnosis. As set out below, the use of this type of tests is imperative in case of special target groups, however, these tests alone are not suitable for informing decisions about long-term measures.

2. To assess the possible scope of long-term measures, it is indispensable to monitor the level of immunisation of the population, that is the extent to which people have become resistant to SARS-CoV-2. Examinations must be two-fold with different rate and frequencies. On the one hand, a broad testing of the population based on representative scientific sampling is needed, aimed at measuring the level of antibodies in the blood after the infection. On the other hand, target groups living or working in confined spaces (health care workers, residents of retirement homes, teaching staff at schools, etc.) must be tested selectively.
   
   In order to mitigate the adverse effects of restrictions and to make epidemic control measures sustainable, it is advised to allow immune (non-susceptible) persons, who no longer spread the virus, return to work and engage in community actions, and in particular encourage their employment in jobs that would normally involve a threat of infection. This approach would also result in an increased capacity for testing, the introduction of further control mechanisms based on measurement data, and allow for a continued and more targeted management of the epidemic.
   
   The proposals presented below suggest complex measures to control the epidemic, including the registry of infected and immune individuals, who shall be granted special permissions, while at the same time they ensure the protection of the susceptible population. When combined, these elements are expected to work towards defeating the epidemic, guaranteeing the protection of public health and creating the necessary conditions for economic growth.

II. Professional aspects of the management of the epidemic

A. Identification of epidemic target groups

For subsequent public health /epidemiologic measures, the following groups need to be identified:

1. infected and infectious (may spread the disease);
   
   
2. susceptible, not yet contracted the disease;
   
   
3. immune, have undergone clinical and laboratory confirmation of the COVID-19 disease;
   
   
4. immune, immunized without symptoms of clinical disease, confirmed by both types of validated tests.

In order to introduce measures of public authorities the separability of the above groups must be ensured until vaccination or effective medicated prevention is available.

Group 1 The PCR-based molecular diagnostic method is clearly suitable for the identification of infectious and/or symptomatic patients and for the detection of the presence of the virus. This test must be performed on patients with clinical symptoms of SARS-CoV-2 infection, and also on all patients hospitalized during the outbreak, combined with eventual serological testing. However, the real-life applicability of PCR-based testing on a wider population is questionable, but full-scale testing of specific communities, e.g. health workers or people in crowded small communities is necessary. Contact tracing and PCR-based testing of individuals tested positive for the virus is also important. In the first acute wave of the epidemic general physical distancing, voluntary quarantine, and the wearing of face masks are the recommended measures to slow the spread of the virus. It is important to avoid panic, fear-mongering and excessive restrictive measures, since 80% of SARS-CoV-2 infections are asymptomatic or show mild symptoms.

Group 2 Vulnerable individuals at high risk for COVID-19 disease (older people and those having an underlying health condition with increased complications), and especially their cohabiting groups and those caring for or visiting them, also require regular PCR-based testing. Both virus testing and serological testing should be fully and regularly performed among people at high risk (health care workers, people living in retirement homes, anyone allowed to return to the community, such as people released from hospital). Prompt isolation and special care of those infected is possible and necessary on these grounds. However, in later stages it is also very important to thoroughly trace and test contacts of identified patients. This and their quarantine is currently the basis for epidemiologic measures, but it should be performed in a more efficient way. The – primarily voluntary – introduction of contact tracing smartphone applications developed or under development by leading info communication technology companies is an important task.

Group 3 and 4 The emergence of these groups is confirmed by scientific publications, that describe the use of blood plasma of recovering patients as a treatment, the appearance of neutralizing antibodies preventing virus infection and reinfection, and the serological tests used to detect them. The results show that immunisation against SARS-CoV-2 virus, that is the development of antibodies occurs in infected individuals, as in the case of other coronaviruses previously known, at least for a “normal” period of months, possibly years.

B. Broad and targeted testing to identify members of epidemic groups

It is an enormous task to rapidly organise the testing of a significant part of the population (preferably using virus-PCR and serological tests at the same time), which is unprecedented in Hungary. At the same time, it is essential to obtain data which are specific to concrete geographical areas and population groups as an indispensable source of information to design well-established epidemiological measures.

Social acceptance of testing can be grounded on widely communicated and professional information. Setting up the technical and organisational background for sampling is a task with previously unknown magnitude, considering that the procedure should be repeatable. When screening for infected persons, targeted PCR testing can help the economical use of some of the reagents.

Quantitative detection of antiviral antibodies should only be performed with widely validated, reliable, high-capacity tests. The testing of individuals with antibodies, who are already virus-free and are immune, should only be repeated infrequently or not repeated at all. Those who are not at risk anymore and do not pose a risk to others should be considered for an official “certificate” that can be used for example for employment purposes.

C. Organisational background and infrastructure

The wide-ranging demand for epidemiological testing and intervention can only be met if the basic organisational, financial, infrastructural and human conditions are put in place with urgency. These can serve as the foundations for selective measurements and interventions required to manage the COVID-19 (and any other similar) epidemic.

It is an important to note that, similarly to military defence, the protection against epidemics needs basic structures and capacities to rely on for the long-term. These should be developed with urgency in particular for contact tracing, sampling, analysis and registry requiring an increase in human resources, infrastructure and funding.

D. Publication of epidemiological measurement data and methods for their usage

It is an important aspect of the COVID-19 epidemic that everyone should be considered a potential source of infection until the opposite has proven likely. Any intervention that is not based on data about the ratio of asymptomatic, mildly symptomatic, virus-free or immune people can only be considered as groping in the dark, and due to their delayed effects and lack of reliable statistics on their impact, they come at a high healthcare and economic cost.

Selective epidemiological measures are based on timely measurements of data on affected social groups, individuals and activities. Based on these data the epidemiological consequences of such measures can be predicted and assessed.

Information collected about infectiveness, immunity or vaccination coverage of different social groups can allow for better targeted restrictions or exemptions. For example, these can be put in place regarding access to public education, commercial or industrial spaces or common living spaces such as dormitories, workers’ hostels, barracks, prisons, etc.

Data on individual immunity status can be used for example:

• to grant selective permission for immune individuals to enter the country; to oblige non-immune inbound travellers for official quarantine or vaccination;
• to employ immune workers in tasks that require frequent social contacting, e.g. border control, epidemiological testing, contact tracing, commercial activities, etc.;
• to decide about fitness for frontline work in healthcare activities;
• to impose selective restrictions or offering selective permissions for individuals at high risk.

Information about the level of immunity of the population against SARS-CoV-2 can widen the range of selective protective measures should the epidemic linger, return or have additional waves. It can not only provide medical, but also economic benefits.

III. Recommendations for the effective management of the pandemic

The SARS-CoV-2 virus is not expected to disappear by the end of the current wave of the pandemic. More waves and the reappearance of the virus are likely. We also have to prepare for the emergence of other epidemics of yet unknown sources (e.g. transmission from animals to humans), as indicated by previous SARS, MERS, Ebola and influenza epidemics. Therefore, it is evident that a one-time plan is not sufficient, and the elaboration of sustainable and permanent protective measures is necessary. The multiplication of the virus raises the possibility of multiple versions of COVID-19 appearing worldwide, which calls for the continuous update of both types of tests.

A. Comprehensive preparation of public health

The preparation concerning the infrastructure and the organisational and human capacities includes the following:

1. considerable reinforcement of the healthcare system;
   
   
2. a permanent epidemic registry with the widest possible scope;
   
   
3. long term prevention measures:
   a, monitoring system
   b, changes aiming at reducing the long-term spread of the virus;
   
   
4. management of the vaccination;
   
   
5. general promotion and education of hygiene on all levels of public education;
   
   
6. continuous and credible communication of the public health consequences of the pandemic, which is based on reliable and evidence-based information, but shall be comprehensible for the widest general audiences, gaining the public’s trust.

B. Reinforcing the healthcare system

Beyond the need for targeted epidemic measures, the current situation caused by the COVID-19 pandemic highlights issues that regards the public healthcare system in general.

1. It is apparent that healthcare systems worldwide were caught unprepared by the pandemic. Significant weakness of even the well-equipped national healthcare systems were revealed. The task of improving the Hungarian healthcare system, to analyse the situation and to draw the conclusions takes time. It is, however, already clear that the social and economic consequences of an underfunded and deteriorated healthcare system are severe in case of epidemics (or in case of any other catastrophe of national scale).
   
   The quick and lasting reinforcement of the healthcare system shall be an important task of both the near and the distant future. The entire structure of the public health system calls in particular for considerable improvement and enlargement. Its management must be organised in a way that enables the conduct of nation-scale operations, and it must be equipped with sufficient and adaptable capacity for testing and intervention during an emergency. Its infrastructure, financial and human resources need to be expanded significantly, including deployable reserves.
   
   
2. It is increasingly important to take precautions for the personal protection of healthcare professionals, especially for those in the frontline, working bedside in hospitals. It is essential to gain their trust and cooperation and keeping them continuously up to date with the latest professional information. Personal protective equipment (PPE) and tests must be provided constantly, their financial support increased significantly, and a system for their psychological support needs to be put in place. By implementing these measures, the exhaustion and mass-scale drop-out of those who play a prominent, often heroic role in battling the pandemic can be prevented. The same measures are applicable for public service providers and the law enforcement.
   
   
3. It is necessary to consult the relevant professional groups continuously, the Hungarian Medical Chamber (MOK) and the Hungarian Union of Medical Societies and Associations (MOTESZ). Their network of experts is essential to organise high-level professional communication and cooperation between those involved in crisis management and medical work.
   
   
4. Beyond the immediate tasks of epidemic control, other collateral healthcare and social issues must be addressed as well. These can influence the course of a possible new wave of infections in the already overburdened and underfunded healthcare system by affecting the non-attendance of patients with chronic disease, the deterioration of screening rigour, the increase in waiting lists, and the delays in diagnostic procedures.

C. Scientific research and development in the field of epidemiology

Scientific research must be reinforced in particular in the following fields:

1. virology research, detection and surveillance of local zoonoses and other threats posed by infectious disease, continuous study and research of virus mutations and the consequent update of diagnostic tests;
   
   
2. measurement research for epidemic control, research for the analysis and prediction of epidemics;
   
   
3. healthcare and disaster management;
   
   
4. small molecule anti-coronavirus drugs, immune defense mechanisms;
   
   
5. humoral and cellular immunity to SARS-CoV-2, investigation of the danger of re-infection and reactivation of the virus;
   
   
6. development of diagnostic tests, research for their mass application including pooling methods;
   
   
7. study of the legal and procedural conditions for mandatory vaccination

Hungarian research and development can make substantial contribution for new developments in the fields of diagnosis and therapy. At the same time, the involvement of scientific researchers and the association and committees of the Hungarian Academy of Sciences is essential for informed government decisions. Their involvement is also fundamental in order to gain the trust of experts and lay people and to provide a continuous channel of communication to the general public. Best practices already in place include the regularly updated collection of COVID-19 related articles on the website of the Academy: https://mta.hu/mta_hirei/akademiai-forrastar-a-covid-19-ellenes-kuzdelemhez-110434 and the widely appreciated webpage established by the young researchers of the Eötvös Loránd Research Network (ELKH) https://koronavirus-kisokos.eu/ that addresses the lay audience.

D. Test of immunity status and the use of immunity verification

In time of epidemics identifying persons with immunity is crucially important both for health care activities and also in order to restart the economy and for the people to return to work. Selective measures require reliable information and the verification of people’s immunity status, that must be based on validated tests.

Verification must rely on a daily updated register of recovered patients and on validated, accredited and widely applied serological tests to identify immune individuals that belong to group 3 and 4 (see section II. A.). The development, the validation and the accreditation of these testing methods must be accelerated in cooperation with the professional and legal experts of the National Institute of Pharmacy and Nutrition (OGYÉI).

Accredited tests and later on validated drugs and vaccines will need to be made available in Hungary in hundreds of thousands or even in millions of doses. Purchasing the appropriate reagents, kits, drugs may prove to be a difficult, since international examples show a lack of availability and a rapid rise in prices. Supporting national efforts for their development is of key importance and shall start immediately.

Vaccination

In case an effective vaccine is developed somewhere in the world, unusual difficulties will have to be faced during its application. There is no relevant Hungarian experience that would support the management of rapid, emergency vaccinations. The management of the mass production of vaccines is an enormous and time consuming task and it is not discussed in this proposal. Beyond the provision of the vaccine, the actual vaccination of a significant part of the population is by itself a specific epidemiological task that needs to be prepared for in advance. It is important to define priority groups and to identify individuals belonging to these groups based on a registry, to organize the vaccinations and to monitor possible side effects.

Recommended order of priority for vaccination groups:

1. healthcare staff, professionals whose work is essential in defence;
   
   
2. highly vulnerable individuals;
   
   
3. susceptible individuals;
   
   
4. individuals with declining immunity (require booster shots).

The COVID-19 pandemic has created a previously unknown and rapidly changing situation around the world. This unknown phenomenon demands swift scientific analysis, in which the public association of the Hungarian Academy of Sciences takes part as well. Accordingly, as new evidence is researched, the proposed measures in this document may have to be updated, and new proposals may be formulated.

Budapest, 22 April 2020

The recommendation was prepared by:

András Falus, Member of the Hungarian Academy of Sciences, Professor Emeritus, Semmelweis University

Gábor Makara, Member of the Hungarian Academy of Sciences, Institute of Experimental Medicine

Ferenc Oberfrank, Managing Director, Institute of Experimental Medicine

Balázs Sarkadi, Member of the Hungarian Academy of Sciences, Research Centre for Natural Sciences, Semmelweis University

András Váradi, Doctor of the Hungarian Academy of Sciences, Research Centre for Natural Sciences,

Zoltán Vokó, Doctor of the Hungarian Academy of Sciences, Semmelweis University