Recent pandemics and informed predictions

The COVID-19 pandemic has not ended, but for most people, life has returned to nearly normal. This is therefore a good time to think about lessons learned from the COVID-19 pandemic as well as from earlier pandemics, and think about what we did well and what we did not do so well. This contemplation resulted in a set of predictions that were presented at the 2024 meeting of the Australian Immunisation Coalition.

Prediction #1. The next pandemic will be a zoonotic respiratory virus, with a caveat

Humans will be immunologically naïve to the virus in part because it will be a zoonotic virus. The virus will need to be able to efficiently transmit from human to human, making a respiratory virus more likely. Further the virus will need to efficiently infect the upper airway. This was the key difference between severe acute respiratory syndrome coronavirus 1 (SARS-CoV, which causes SARS) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, which causes COVID-19) since both use ACE2 as a host cell receptor but only SARS-CoV-2 was able to infect and transmit from the upper airway.

The caveat is that there may be surprises still. Two new feline and canine coronaviruses were recently identified, with novel features. One was identified in children in Malaysia with respiratory illness. It contained genetic information from canine, feline and swine coronaviruses (CoVs).¹ These viruses all use the same receptor (aminopeptidase N) and can fairly easily cross species. The virus has never been found in nature. Although there is no evidence for interhuman transmission, humans possess no immunity to these viruses. The second novel CoV was identified in cats in Cyprus.² Feline CoV is an enteric pathogen that is easily transmitted from cat to cat. Occasionally, mutations occur in a persistently infected host that results in a change in cellular tropism from epithelial cells to macrophages (feline infectious peritonitis virus, FIPV). FIPV is highly lethal, but does not transmit from cat to cat. Recently, an outbreak of FIPV occurred on Cyprus. This was not supposed to occur because FIPV is not transmissible. However, this virus was FIPV with a recombinant version of a pantropic canine CoV S protein. Thus, this virus is not completely new, but has gained the ability to transmit by recombination and is highly virulent.

Prediction #2. Surveillance will be critical for identifying potential pandemic viruses

Surveillance is critical to identify possibilities with a One Health approach in mind.³ Surveillance will include: (1) surveillance at the human–wildlife interface; (2) surveillance for human and wildlife antibody responses to high-risk pathogens at sites of high zoonotic cross over; and (3) surveillance of patients with pneumonia of unknown etiology in high-risk areas. Surveillance has to be focused. Otherwise, there will be information overload.

We will need to have a plan for use of the information. Several studies prior to 2019 demonstrated the presence of bat SARS-like CoVs able to infect human cells but this information was not used to facilitate planning. In retrospect, could we have used these data for vaccine or antiviral therapy development? It seems unlikely that either approach would have received funding prior to 2019.

Prediction #3. We will know more about the agent causing the next pandemic than we think

In the beginning of the COVID-19 pandemic, there was fear of the unknown, especially given the 2–3% mortality of COVID-19. However, it was quickly learned that much was known about the replication strategy of the virus, based on coronavirus research performed over the preceding 50 years. The replication strategy of these viruses was largely understood and reverse genetics systems were established for manipulating the virus.⁴ Many potential targets for anti-viral therapy were known (protease, polymerase). For example, protease inhibitors active against FIPV had been identified and shown to reduce mortality from 100 to 50%.⁵ Vaccines had been developed for several coronaviruses that caused disease in farm and companion animals, although many of these were ineffective.⁶ Knowledge gained from these efforts helped to guide SARS-CoV-2 vaccine development.

Prediction #4. We will make medical mistakes

Medical mistakes were made in the COVID-19 pandemic. For example, heavy use of ventilators early in the pandemic resulted in poor outcomes. This mistake was corrected only when it was realised that the hypoxia observed in the early stages of the infection resulted from vascular damage rather than lung damage.⁷ Prone positioning of patients in the Intensive Care Unit (ICU) was also found to improve outcomes. A second example was that our initial understanding of transmission was incorrect. The important role of aerosol transmission, including from asymptomatic and presymptomatic individuals was not initially appreciated.⁸ Thus, mask usage was not encouraged until relatively later in the pandemic.⁹

Prediction #5. We will make mistakes in communication

Communication during the COVID-19 pandemic to the public was often flawed. Many of these errors occurred because new information was available on almost a daily basis. For example, initially, pregnancy was not considered a risk factor for severe COVID-19. Then it became apparent that fetuses were not infected, but the placenta could be. Finally, we learned that COVID-19 outcomes in pregnancy outcomes were worse when compared to uninfected nonpregnant women of the same age.¹⁰ Another example, as mentioned above, was recommendations about mask usage changed as we understood transmission better. However, this change in recommendations as knowledge was gained was not clearly conveyed to the general public. A third example was that school closures were continued for longer than was justified by the data. We learned that communication with public will need to be nuanced.

Prediction #6. We will make effective uses of scientific advances

Advances partly derived from the COVID-19 pandemic will be used in the future. Correlates of protection are better but imperfectly understood. We learned that pre-existing immunity is protective even in the absence of robust neutralising antibodies.¹¹ We learned more about the maturation of the antibody response in memory B cells, and how this response broadens with time even in the absence of additional stimulation.¹² We learned about the importance of non-neutralising antibodies and T cells in protection against CoV infection. We learned about the use of wastewater to monitor virus spread, especially when virus testing is diminished.¹³ We learned about the value of human challenge trials in understanding COVID-19 pathogenesis.¹⁴

Prediction #7. A future pandemic will bring out the opportunists

Individuals and groups will use fear as a tool to gain power and money. For example, anti-vaccination websites sold unproven therapies such as ivermectin, which led to profits. We learned that public health authorities and scientists need to actively refute these claims.

Prediction #8. There will be human altruism

This was well illustrated during the COVID-19 pandemic, where healthcare workers, including physicians, nurse, medical assistants, ambulance drivers, cafeteria workers, clinical and research laboratory personnel, etc., many of whom were underpaid, worked long hours under conditions that exposed them to SARS-CoV-2. They were as critical as those who provide basic services – police, fire fighters, custodians, bus drivers, etc.

Prediction #9. There will be better availability of vaccines worldwide

Countries like India were able to produce large amounts of vaccines, increasing accessibility worldwide. This ameliorated some of the global inequalities in terms of vaccine. Organisations such as the Coalition for Epidemic Preparedness Innovations (CEPI) are stockpiling vaccines. This approach has limitations because vaccines expire and we do not know what will actually be needed against the next pathogen. We also learned that vaccines can be produced very rapidly and safely. However, it will be critical to overcome vaccine hesitancy.

Prediction #10. There will be cheap and readily available antiviral therapies (aspirational)

An oral anti-viral therapy would be more readily accepted by general populations than are vaccines. In terms of CoV therapies, we learned that a single protease inhibitor might be active against many CoVs. However, we still need to learn how to produce these anti-virus therapies in sufficient amounts and at low costs to be useful in low-income countries.

Prediction #11. There will be less ethnic, racial and economic disparities in access to vaccines and therapy (aspirational)

There were differences in access to vaccines and therapies, depending on ethnic, racial and economic factors as well as differences in acceptability. We learned that minimising these disparities was important in decreasing total virus load in the population as well as reducing disease the group in question.

Prediction #12. If the next pandemic is caused by a CoV, it will not be a sarbecovirus

MERS-CoV, the cause of the Middle East Respiratory Syndrome coronavirus, is a camel virus with little interhuman transmission except in hospital and perhaps household settings.¹⁵ If MERS-CoV became more transmissible, it could cause an epidemic or pandemic because humans do not have immunity to this virus. However, from the COVID-19 pandemic we learned that it is not the known CoVs (such as SARS-CoV) that are a problem, but rather unknown CoV, such as SARS-CoV-2 in the case of the COVID-19 pandemic. Thus MERS-like CoV in bats, camelids and perhaps other animals must be high on the list of pathogens that require vigilance. An additional concern is that some MERS-like CoV can use ACE2 as receptor, which we know allows for interhuman transmission.