Pandemic preparedness: On the efficacy of non-pharmaceutical interventions in COVID-19 and about approaches to predict future pandemic viruses.

With three major viral pandemics over the last 100 years, namely the Spanish flu, AIDS and COVID-19 each claiming many millions of lives, pandemic preparedness has become an important issue for public health. The economic, social and political consequences of the upheaval caused by such pandemics also represent a major challenge for governments with respect to sustainable development goals. The field of pandemic preparedness is vast and the current article can only address selected aspects. The article looks first backwards and addresses the question of the efficacy of non-pharmaceutical interventions (NPI) on the trajectory of the COVID-19 pandemic. The article looks then forward by asking to what extent viral candidates for future pandemics can be predicted by virome analyses from metagenome and transcriptome sequencing, by focusing on the virome from specific animal species and using ecological and epidemiological data about spillover viral infections in veterinary and human medicine. As a comprehensive overview on pandemic preparedness is beyond the capacity of a single reviewer, only selected topics will be discussed using recent key scientific publications. Since COVID-19 has not run its course, a computational program able to predict the future evolution of SARS-CoV-2 is mentioned that could assist proactive mRNA vaccine developments against possible future variants of concern. Ending the COVID-19 epidemic necessitates mucosal vaccines that can suppress the transmission of SARS-CoV-2 and therefore this article closes by discussing a promising and versatile protein nanoparticle experimental vaccine approach for inhalation that does not depend on needles nor a cold chain for distribution.

Avian influenza virus cross-infections as test case for pandemic preparedness: From epidemiological hazard models to sequence-based early viral warning systems.

Pandemic preparedness starts with an early warning system of viruses with a pandemic potential. Based on information collected in a multitude of surveys, hazard models were developed identifying influenza viruses presenting a pandemic threat. Scores are attributed for 10 viral traits by expert panels which identified avian influenza viruses (AIV) belonging to subtypes H7N9 and H5N1 as representing the greatest pandemic risk. In 2013, more than 100 human cases infected with AIV H7N9 were observed in China. Case fatality rate (CFR) was high (27%), but the human-to-human transmission rate was low and by serological evidence H7N9 did not spread widely. Nevertheless, until 2019 more than 1500 H7N9 patients were identified characterized by a high CFR of 39%. Serology demonstrated that mild infections with H7N9 were widespread. In 2003, more than 400 people experienced AIV H7N7 cross-infection causing mainly conjunctivitis during a large poultry epidemic in The Netherlands. Between 1996 and 2019, a total of 881 human infections with avian H5N1 viruses were documented showing a CFR of 52%. Outbreaks were centred on South East Asia and showed close associations with epizootics in poultry. Mutations predisposing to human cross-infections were identified in the haemagglutinin (HA) and the RNA polymerase subunit PB2 of human H7N9 isolates. Human H5N1 isolates showed mutations in the receptor binding domain of HA and transmission in mammals could be obtained by as few as four additional aa changes introduced experimentally. Researchers have defined viral point mutations in HA, PB2 and the nucleoprotein NP that allowed AIV to cross the species barrier to mammals with respect to receptor recognition, RNA replication and escape from innate immunity respectively. Based on this insight a sequence-based early warning system for AIV preadapted to human transmission could be envisioned. Mink farms and live poultry markets are prime targets for such sequencing efforts.

The human microbiome project at ten years - some critical comments and reflections on "our third genome", the human virome.

The Human Microbiome Project (HMP) has raised great expectations claiming the far-reaching influence of the microbiome on human health and disease ranging from obesity and malnutrition to effects going well beyond the gut. So far, with the notable exception of fecal microbiota transplantation in Clostridioides difficile infection, practical application of microbiome intervention has only achieved modest clinical effects. It is argued here that we need criteria for the link between microbiome and disease modelled on the links between pathogens and infectious disease in Koch's postulates. The most important question is whether the microbiome change is a cause of the given disease or a consequence of a pathology leading to disease where the microbiome change is only a parallel event without a causal connection to the disease - in philosophical parlance, an epiphenomenon. Also discussed here is whether human virome research is a necessary complement to the microbiome project with a high potential for practical applications.

Non-A to E hepatitis in children: Detecting a novel viral epidemic during the COVID-19 pandemic.

During the COVID-19 pandemic, two further novel viral epidemics were described in 2022, monkeypox virus infections in men having sex with men and non-A to E hepatitis in children. The latter occurred in the first half of 2022 with about 1000 cases worldwide, necessitating liver transplantation in 5% and causing death in 2% of patients. It took some effort to clarify the cause of the novel hepatitis epidemic. Researchers were confronted with a polymicrobial viral infection consisting of an adenovirus-associated virus type 2 (AAV2) infection, co-occurring with either human adenovirus type 41 (HAdV41) or herpesvirus infections; most prominently human herpesvirus type 6 (HHV-6). AAV-2, a small Dependovirus of the Parvovirus family, needs these helper viruses for its replication. AAV2 is used as a vector for liver-targeting gene therapy but was not previously known to cause acute hepatitis. HAdV41 and HHV-6 are mostly known to cause diarrhoea and febrile illnesses associated with skin rashes in children, respectively. Except for a few case reports of HHV-6 hepatitis, HAdV and HHV-6 are mostly known as major pathogens in immunosuppressed transplantation patients. A potential role of SARS-CoV-2 has also been discussed but the most popular hypothesis involves an indirect role of the COVID-19 pandemic for this novel disease. Exposure to HHV-6 infections occurs nearly quantitatively during the first year of life. Social distancing measures, followed by the lifting of these measures in 2022 might have caused a delayed exposure to multiple, normally benign childhood viral infections eliciting a dysregulated immune response with pathological effects for liver cells. In the fall of 2022, when these conditions were not longer met, case numbers dwindled. The hypothesis of an unequilibrated immune response instead of intrinsic cytopathic activity of the implicated viruses is further supported by the enrichment of a particular HLA allele in cases over controls.

Viral infections at the animal-human interface-Learning lessons from the SARS-CoV-2 pandemic.

This Lilliput explores the current epidemiological and virological arguments for a zoonotic origin of the COVID-19 pandemic. While the role of bats, pangolins and racoon dogs as viral reservoirs has not yet been proven, a spill-over of a coronavirus infection from animals into humans at the Huanan food market in Wuhan has a much greater plausibility than alternative hypotheses such as a laboratory virus escape, deliberate genetic engineering or introduction by cold chain food products. This Lilliput highlights the dynamic nature of the animal-human interface for viral cross-infections from humans into feral white tail deer or farmed minks (reverse zoonosis). Surveillance of viral infections at the animal-human interface is an urgent task since live animal markets are not the only risks for future viral spill-overs. Climate change will induce animal migration which leads to viral exchanges between animal species that have not met in the past. Environmental change and deforestation will also increase contact between animals and humans. Developing an early warning system for emerging viral infections becomes thus a societal necessity not only for human but also for animal and environmental health (One Health concept). Microbiologists have developed tools ranging from virome analysis in key suspects such as viral reservoirs (bats, wild game animals, bushmeat) and in humans exposed to wild animals, to wastewater analysis to detect known and unknown viruses circulating in the human population and sentinel studies in animal-exposed patients with fever. Criteria need to be developed to assess the virulence and transmissibility of zoonotic viruses. An early virus warning system is costly and will need political lobbying. The accelerating number of viral infections with pandemic potential over the last decades should provide the public pressure to extend pandemic preparedness for the inclusion of early viral alert systems.

Pandemic potential of poxviruses: From an ancient killer causing smallpox to the surge of monkeypox.

Smallpox caused by the variola virus (VARV) was one of the greatest infectious killers of mankind. Historical records trace back smallpox for at least a millennium while phylogenetic analysis dated the ancestor of VARV circulating in the 20th century into the 19th century. The discrepancy was solved by the detection of distinct VARV sequences first in 17th-century mummies and then in human skeletons dated to the 7th century. The historical records noted marked variability in VARV virulence which scientists tentatively associated with gene losses occurring when broad-host poxviruses narrow their host range to a single host. VARV split from camel and gerbil poxviruses and had no animal reservoir, a prerequisite for its eradication led by WHO. The search for residual pockets of VARV led to the discovery of the monkeypox virus (MPXV); followed by the detection of endemic smallpox-like monkeypox (mpox) disease in Africa. Mpox is caused by less virulent clade 2 MPXV in West Africa and more virulent clade 1 MPXV in Central Africa. Exported clade 2 mpox cases associated with the pet animal trade were observed in 2003 in the USA. In 2022 a world-wide mpox epidemic infecting more than 80,000 people was noted, peaking in August 2022 although waning rapidly. The cases displayed particular epidemiological characteristics affecting nearly exclusively young men having sex with men (MSM). In contrast, mpox in Africa mostly affects children by non-sexual transmission routes possibly from uncharacterized animal reservoirs. While African children show a classical smallpox picture, MSM mpox cases show few mostly anogenital lesions, low-hospitalization rates and 140 fatal cases worldwide. MPXV strains from North America and Europe are closely related, derived from clade 2 African MPXV. Distinct transmission mechanisms are more likely causes for the epidemiological and clinical differences between endemic African cases and the 2022 epidemic cases than viral traits.

Do we need nasal vaccines against COVID 19 to suppress the transmission of infections?

Covid-19 vaccines have within the first year prevented about 14 million deaths but did not induce a strong mucosal immune response. Data from US, UK, Singapore and Israel showed a variable and mostly modest effects of vaccination on virus excretion during breakthrough infections. Contact studies showed decreased transmission of infection from vaccinated index cases, but the effect varied according to dominant virus type, with study type and the nature of the contact group and diminished with time after vaccination. Some researchers suspect that it is unlikely to stop the pandemic with injected vaccines alone. Promising animal experiments were conducted with mucosal vaccines. Mice nasally immunized with a chimpanzee adenovirus vector mounted a mucosal immune response, were protected against viral challenge after a single vaccine dose and suppressed nasal replication of the challenge virus. Phage T4 expressing SARS-CoV-2 spike and nucleocapsid induced a sterilizing lung immunity in nasally vaccinated mice. Also hamsters intranasally immunized with the prefusion-stabilized spike protein showed no infectious virus in nasal turbinates upon challenge. Other studies showed that intranasal vaccination with an adenovirus vaccine reduced but did not eliminated viral transmission from infected to naïve hamsters. Intranasal vaccination of rhesus macaques with adenovirus vaccines also substantially reduced or even suppressed viral replication in the upper and lower respiratory tract. Human data on mucosal SARS-CoV-2 vaccines are so far limited to safety and immunogenicity studies. Aerosolized adenovirus vaccines given either as a booster or as primary immunization were safe and induced similar or superior immune response than injected vaccines while an aerosolized influenza vectored vaccine induced only a weak humoral and cellular immune response. Overall 100 mucosal SARS-CoV-2 vaccines are in development and 20 are in clinical trials. First human trials demonstrate that this will not be an easy task.

On the role of hypotheses in science.

Scientific research progresses by the dialectic dialogue between hypothesis building and the experimental testing of these hypotheses. Microbiologists as biologists in general can rely on an increasing set of sophisticated experimental methods for hypothesis testing such that many scientists maintain that progress in biology essentially comes with new experimental tools. While this is certainly true, the importance of hypothesis building in science should not be neglected. Some scientists rely on intuition for hypothesis building. However, there is also a large body of philosophical thinking on hypothesis building whose knowledge may be of use to young scientists. The present essay presents a primer into philosophical thoughts on hypothesis building and illustrates it with two hypotheses that played a major role in the history of science (the parallel axiom and the fifth element hypothesis). It continues with philosophical concepts on hypotheses as a calculus that fits observations (Copernicus), the need for plausibility (Descartes and Gilbert) and for explicatory power imposing a strong selection on theories (Darwin, James and Dewey). Galilei introduced and James and Poincaré later justified the reductionist principle in hypothesis building. Waddington stressed the feed-forward aspect of fruitful hypothesis building, while Poincaré called for a dialogue between experiment and hypothesis and distinguished false, true, fruitful and dangerous hypotheses. Theoretical biology plays a much lesser role than theoretical physics because physical thinking strives for unification principle across the universe while biology is confronted with a breathtaking diversity of life forms and its historical development on a single planet. Knowledge of the philosophical foundations on hypothesis building in science might stimulate more hypothesis-driven experimentation that simple observation-oriented "fishing expeditions" in biological research.

On opinion, freedom of speech and its responsibilities.

Plato and Aristotle place opinion intermediate between knowledge and ignorance with all opinions under the suspicion of error. Kant summarized that opinion is a consciously insufficient judgement, subjectively and objectively. Belief is subjectively sufficient, but is recognized as being objectively insufficient. Only knowledge is subjectively and objectively sufficient. Despite this philosophically doubtful value of opinions, thinkers such as Milton, Locke, Montesquieu and Mill maintain that the freedom of opinion and speech are the basis of open societies but find limits when it represents a definite risk of damage, either to an individual or to the public. Also the UN Covenant on Civil and Political Rights proclaims the right to hold opinions without interference provided that it respects the rights or reputations of others and does not interfere with the protection of public health. Hate speech and propaganda for war are expressively prohibited. Postwar US politicians formulated the position that every man has a right to his own opinion, but no man has a right to be wrong in his facts. The impact of this discussion on opinions about control measures of the COVID-19 pandemic is explored in this editorial.

What is truth - in science and beyond.

Truth is threatened in our societies and one might wish that scientists should stand up for truth, but in order to do so, one needs to know what is truth and how it can be recognized. The oldest and most widely accepted concept of truth is the Correspondence Theory requesting a fit of propositions and reality. In the Coherence Theory truth is a consistent property of a whole system of propositions. In the Pragmatic Theory truth works in practical terms. Scientists have defined criteria to verify true statements by experiments and by the simplicity of theories. Aristotle proposed parsimony claiming the superiority of theories which derive from fewer hypotheses. David Hume suggested probability arguments to assess the force of evidence. Nicolai Hartmann elaborated a model based on the congruence of a priori logical arguments with a posteriori empirical observations. Karl Popper introduced the falsification of testable theories as a way to better theories. The analysis shows that scientific and medical research uses classical philosophical criteria of truth in their daily work. Humanities use different, hermeneutic criteria of truth. Finally, societies need for their coherence a dialectic approach to truth based on honest discussion of opposing views.

COVID-19: Omicron - the latest, the least virulent, but probably not the last variant of concern of SARS-CoV-2.

The Omicron variant rapidly became the dominant SARS-CoV-2 strain in South Africa and elsewhere. This review explores whether this rise was due to an increased transmission of the variant or its escape from population immunity by an extensively mutated spike protein. The mutations affected the structure of the spike protein leading to the loss of neutralization by most, but not all, therapeutic monoclonal antibodies. Omicron also shows substantial immune escape from serum antibodies in convalescent patients and vaccinees. A booster immunization increased, however, the titre and breadth of antiviral antibody response. The cellular immune response against Omicron was largely preserved explaining a satisfying protection of boosted vaccinees against severe infections. Clinicians observed less severe infection with Omicron, but other scientists warned that this must not necessarily reflect less intrinsic virulence. However, in animal experiments with mice and hamsters, Omicron infections also displayed a lesser virulence than previous VOCs and lung functions were less compromised. Cell biologists demonstrated that Omicron differs from Delta by preferring the endocytic pathway for cell entry over fusion with the plasma membrane which might explain Omicron's distinct replication along the respiratory tract compared with Delta. Omicron represents a distinct evolutionary lineage that deviated from the mainstream of evolving SARS-CoV-2 already in mid-2020 raising questions about where it circulated before getting widespread in December 2021. The role of Omicron for the future trajectory of the COVID-19 pandemic is discussed.

The beginning and ending of a respiratory viral pandemic-lessons from the Spanish flu.

The COVID-19 pandemic goes into its third year and the world population is longing for an end to the pandemic. Computer simulations of the future development of the pandemic have wide error margins and predictions on the evolution of new viral variants of SARS-CoV-2 are uncertain. It is thus tempting to look into the development of historical viral respiratory pandemics for insight into the dynamic of pandemics. The Spanish flu pandemic of 1918 caused by the influenza virus H1N1 can here serve as a potential model case. Epidemiological observations on the shift of influenza mortality from very young and old subjects to high mortality in young adults delimitate the pandemic phase of the Spanish flu from 1918 to 1920. The identification and sequencing of the Spanish flu agent allowed following the H1N1 influenza virus after the acute pandemic phase. During the 1920s H1N1 influenza virus epidemics with substantial mortality were still observed. As late as 1951, H1N1 strains of high virulence evolved but remained geographically limited. Until 1957, the H1N1 virus evolved by accumulation of mutations ('antigenic drift') and some intratypic reassortment. H1N1 viruses were then replaced by the pandemic H2N2 influenza virus from 1957, which was in 1968 replaced by the pandemic H3N2 influenza virus; both viruses were descendants from the Spanish flu agent but showed the exchange of entire gene segments ('antigenic shift'). In 1977, H1N1 reappeared from an unknown source but caused only mild disease. However, H1N1 achieved again circulation in the human population and is now together with the H3N2 influenza virus an agent of seasonal influenza winter epidemics.

COVID-19 and children: medical impact and collateral damage.

Children mostly experience mild SARS-CoV-2 infections, but the extent of paediatric COVID-19 disease differs between geographical regions and the distinct pandemic waves. Not all infections in children are mild, some children even show a strong inflammatory reaction resulting in a multisystem inflammatory syndrome. The assessments of paediatric vaccination depend on the efficacy of protection conferred by vaccination, the risk of adverse reactions and whether children contribute to herd immunity against COVID-19. Children were also the target of consequential public health actions such as school closure which caused substantial harm to children (educational deficits, sociopsychological problems) and working parents. It is, therefore, important to understand the transmission dynamics of SARS-CoV-2 infections by children to assess the efficacy of school closures and paediatric vaccination. The societal restrictions to contain the COVID-19 pandemic had additional negative effects on children's health, such as missed routine vaccinations, nutritional deprivation and lesser mother-child medical care in developing countries causing increased child mortality as a collateral damage. In this complex epidemiological context, it is important to have an evidence-based approach to public health approaches. The present review summaries pertinent published data on the role of children in the pandemic, whether they are drivers or followers of the infection chains and whether they are (after elderlies) major sufferers or mere bystanders of the COVID-19 pandemic.

Can a combination of vaccination and face mask wearing contain the COVID-19 pandemic?

The COVID-19 pandemic is going into its third year with Europe again being the focus of major epidemic activity. The present review tries to answer the question whether one can come to grip with the pandemic by a combination of vaccinations and non-pharmaceutical interventions (NPIs). Several COVID-19 vaccines are of remarkable efficacy and achieve high protection rates against symptomatic disease, especially severe disease, but mathematical models suggest that the current vaccination coverage in many countries is insufficient to achieve pandemic control. NPIs are needed as complementary measures because recent research has also revealed the limits of vaccination alone. Here, we review the evidence for efficacy of face mask wearing in various settings. Overall pooled analysis showed significant reduction in COVID-19 incidence with mask wearing, although heterogeneity between studies was substantial. Controlled trials of mask wearing are difficult to conduct, separating mask wearing effects in population studies from the impact of other NPIs is challenging and the efficacy of masks depend on mask material and mask fit. The combination of vaccination and mask wearing is potentially synergistic since vaccination protects so far well from disease development (the omicron variant is currently an unknown) but immunity from infection wanes over few months after vaccination. In comparison, masks interfere with the virus transmission process at a level of a physical barrier independent of coronavirus variant. Vaccination and masks are much less costly to apply than other NPI measures which are associated with high economic and social costs, but paradoxically both measures are the target of a vocal opposition by a sizable minority of the society. In parallel with biomedical research, we need more social science research into this opposition to guide political decisions on how to end the pandemic.

mRNA vaccines against COVID-19: a showcase for the importance of microbial biotechnology.

Pfizer-BioNTech and Moderna developed in record time mRNA vaccines against COVID-19 of high efficacy. The modest protection achieved with a similarly designed mRNA from CureVac underlines the importance of biotechnological details in formulation such as replacement of uridine by pseudouridine in the mRNA encoding the SARS-CoV-2 spike protein or the lipid composition of the nanoparticle coating the mRNA. Phase 3 vaccine trials and vaccine studies in special subject groups as well observational studies in whole populations confirmed the real-world vaccine efficacy against symptomatic disease, particularly against severe COVID-19 cases and to a lesser extent against mild SARS-CoV-2 infections. mRNA vaccine protection extended also to the alpha and beta variant viruses. The surge of delta variants led to an increase of infections and cases even in populations which achieved high vaccine coverage. This efficacy decline resulted to a lesser extent from a weaker neutralization of the delta variant but mostly from a waning vaccine protection over time. Data from Israel documented the efficacy of a third 'booster' injection 5 months after the second injection in older segments of the population. Adverse reactions consisted of transient injection site pain, headache, muscle pain, fatigue, fever and chills. Extensive surveillance studies documented a good safety profile revealing only a non-significant increase in transient facial nerve paralysis and a significant, but modest increase in myocarditis in vaccinated young males that was lower than the myocarditis risk induced by SARS-CoV-2 infection.

The Influence of FUT2 and FUT3 Polymorphisms and Nasopharyngeal Microbiome on Respiratory Infections in Breastfed Bangladeshi Infants from the Microbiota and Health Study.

Acute respiratory infections (ARIs) are one of the most common causes of morbidity and mortality in young children. The aim of our study was to examine whether variation in maternal FUT2 (α1,2-fucosyltransferase 2) and FUT3 (α1,3/4-fucosyltransferase 3) genes, which shape fucosylated human milk oligosaccharides (HMOs) in breast milk, are associated with the occurrence of ARIs in breastfed infants as well as the influence of the nasopharyngeal microbiome on ARI risk. Occurrences of ARIs were prospectively recorded in a cohort of 240 breastfed Bangladeshi infants from birth to 2 years. Secretor and Lewis status was established by sequencing of FUT2/3 genes. The nasopharyngeal microbiome was characterized by shotgun metagenomics, complemented by specific detection of respiratory pathogens; 88.6% of mothers and 91% of infants were identified as secretors. Maternal secretor status was associated with reduced ARI incidence among these infants in the period from birth to 6 months (incidence rate ratio [IRR], 0.66; 95% confidence interval [CI], 0.47 to 0.94; P = 0.020), but not at later time periods. The nasopharyngeal microbiome, despite precise characterization to the species level, was not predictive of subsequent ARIs. The observed risk reduction of ARIs among infants of secretor mothers during the predominant breastfeeding period is consistent with the hypothesis that fucosylated oligosaccharides in human milk contribute to protection against respiratory infections. However, we found no evidence that modulation of the nasopharyngeal microbiome influenced ARI risk. IMPORTANCE The observed risk reduction of acute respiratory infections (ARIs) among infants of secretor mothers during the predominant breastfeeding period is consistent with the hypothesis that fucosylated oligosaccharides in human milk contribute to protection against respiratory infections. Respiratory pathogens were only weak modulators of risk, and the nasopharyngeal microbiome did not influence ARI risk, suggesting that the associated protective effects of human milk oligosaccharides (HMOs) are not conveyed via changes in the nasopharyngeal microbiome. Our observations add to the evidence for a role of fucosylated HMOs in protection against respiratory infections in exclusively or predominantly breastfed infants in low-resource settings. There is no indication that the nasopharyngeal microbiome substantially modulates the risk of subsequent mild ARIs. Larger studies are needed to provide mechanistic insights on links between secretor status, HMOs, and risk of respiratory infections.

Host-modifying drugs against COVID-19: some successes, but not yet the breakthrough.

After reviewing antiviral drugs (Brüssow Environmental Microbiology 2021) the present review summarizes the results of clinical trials with host-modifying drugs in COVID-19 patients. Clinical benefits were observed with different immunomodulators. The variable outcomes of trials with the interleukin 6 receptor inhibitor tocilizumab demonstrated that treatment benefits might only be present in specific subgroups of patients or in specific infection stages. A meta-analysis of trials with the interleukin 1 receptor antagonist anakinra showed a survival benefit only in patients with hyperinflammation. The Janus kinase inhibitor baricitinib is an anti-inflammatory treatment that showed a clinical benefit in hospitalized patients who do not yet need supplementary oxygen. In contrast, the corticosteroid dexamethasone showed mortality reducing effects that were limited to patients on ventilation or in need of supplementary oxygen. Therapeutic dose of anticoagulation met the criteria for inferiority in severe cases, but showed a small survival benefit in non-severe COVID-19 patients. Large trials with colchicine showed a small or no survival benefit. Azithromycin, an antibiotic with immunomodulatory activity, showed no effects in numerous clinical trials. The trials showed a clear need for new drugs instead of repurposed drugs and drugs that specifically target the SARS-CoV-2 virus or the pathology developing in COVID-19 patients.

Clinical trials with antiviral drugs against COVID-19: some progress and many shattered hopes.

Vaccines and drugs are the cornerstones in the fight against the SARS-CoV-2 pandemic. While vaccines were a success story, the development of antiviral drugs against SARS-CoV-2 turned out to be difficult. For an accelerated use of antivirals in the clinic, most SARS-CoV-2 antivirals represented repurposed drugs. The present article summarizes the outcomes of clinical trials with antiviral drugs in COVID-19 patients. Many antiviral drugs failed to demonstrate beneficial effects or showed mixed results. One reason for the low success rate of clinical trials was shortcomings of antiviral tests in cell culture systems and another reason was the abundance of ill-coordinated and underpowered clinical trials. However, large pragmatic clinical trials particularly of the British RECOVERY trial series demonstrated that even under emergency situation drug trials can be conducted in a timely way such that the therapy of COVID-19 patients can be based on evidence basis instead on expert opinion or even worse on political pressure.

What we can learn from the dynamics of the 1889 'Russian flu' pandemic for the future trajectory of COVID-19.

A study of the contemporary medical literature for patient symptoms from the so-called 'Russian flu' pandemic from 1889 revealed clinical observations that resemble COVID-19 (Brüssow and Brüssow, 2021, Microb Biotechnol). If one accepts the hypothesis that this pandemic was a prior coronavirus epidemic, the dynamics of the 'Russian flu' from 1889 might give us some ideas about the future trajectory of the COVID-19 pandemic. The present report compiles and reviews the contemporary data published on the temporal and geographical spread of the 'Russian flu', its epidemic wave structure and possible later resurgence. The historical record of past pandemics might thus provide us not with predictions, but 'retrodictions' on possible future scenarios for the COVID-19 pandemic.

Clinical evidence that the pandemic from 1889 to 1891 commonly called the Russian flu might have been an earlier coronavirus pandemic.

Contemporary medical reports from Britain and Germany on patients suffering from a pandemic infection between 1889 and 1891, which was historically referred to as the Russian flu, share a number of characteristics with COVID-19. Most notable are aspects of multisystem affections comprising respiratory, gastrointestinal and neurological symptoms including loss of taste and smell perception; a protracted recovery resembling long covid and pathology observations of thrombosis in multiple organs, inflammation and rheumatic affections. As in COVID-19 and unlike in influenza, mortality was seen in elderly subjects while children were only weakly affected. Contemporary reports noted trans-species infection between pet animals or horses and humans, which would concur with a cross-infection by a broad host range bovine coronavirus dated by molecular clock arguments to an about 1890 cross-species infection event.