Conquering Pandemics

 

 The Race to Conquer Pandemics 

Viruses are neither unambiguously alive nor dead; they exist in a dubious state less than alive (they cannot replicate without hijacking the machinery to reproduce from within a living cell) yet once activated within a host cell they replicate rapidly and pass their genetic material to future generations. 

There is one characteristic of viruses that is indisputable: they evolve faster than almost anything on the planet (HIV, the human immunodeficiency virus, holds the record as the highest recorded mutation rate known). This century produced more new viruses of a global concern than ever before. Viruses are multiplying faster than in the past. Add the explosive globalization of economic and social activity and future pandemics could overwhelm civilization. With the unprecedented response to COVID-19, the world's virologists have the opportunity to forestall, even block, future potential pandemics. 

COVID-19 highlighted how important rapid real-time responses are to combat pandemics as new viruses appear and mutate. At the outset of the pandemic, the United States was ill-prepared to control COVID-19. Research and biomanufacturing were constrained by single-purpose equipment designed and built with mass production rather than adaptability in mind (compare a 3D printer with a room full of equipment made for producing a single part). 

It took the novel virus COVID-19 to initiate the most aggressive global vaccination research ever undertaken. The Pfizer vaccine took just one year to develop compared to the previous record of four years set by the mumps vaccine. Scientists had a head start compared to mumps. Coronaviruses were well known, there are hundreds of them including some that cause common colds. In addition, the technology to create man-made viruses has existed for two decades: a poliovirus was synthesized in 2002 using research focused on biowarfare countermeasures. In November of 2003, a team of scientists in Maryland built a virus strain that was 100% identical to a natural virus. Synthetic vaccines would inevitably follow.

Despite all the scientific advancements, the primary defense against a pandemic was to disengage people from one another. Most of the world chose to impose lockdowns of varying degrees and take the usual precautions to avoid spreading viruses. People were told to stay home except for essential purposes. Educational classes were conducted remotely, social and religious gatherings were prohibited or restricted. Economic and social life was suppressed. 

Lockdowns Evoked Both Proponents and Opponents   

The World Health Organization (WHO) chose not to recommend lockdown fearing it would have a disproportionately detrimental impact on the most disadvantaged segments of society. WHO envoy David Nabarro stated WHO’s position, “The only time we believe a lockdown is justified is to buy you time to reorganize, regroup, rebalance your resources, protect your health workers who are exhausted, but by and large, we’d rather not do it.” The US had no cohesive national plan to combat the pandemic. Unlike many other countries mitigation measures were left to state and local governments. A number of countries reacted quickly and effectively.

New Zealand locked down “hard” early in the pandemic and reopened with virtually no restrictions in early June 2020, just four months after the pandemic was widely recognized. Twelve countries (including New Zealand) currently have no COVID-19 cases. In those countries,  lockdowns were limited to buying time to do what WHO advocated. Other countries were able to open economic and social life early without extended lockdowns and few COVID-19 cases and deaths by restricting travel in and out of "quarantined" countries or regions.  

Nevertheless, most of the developed world relied on lockdowns in an attempt to isolate infected people and otherwise minimize the opportunities for the virus to spread. Whether justified or not lockdowns did save lives but precipitated significant economic and social catastrophes which are certain to outlast the pandemic. There are better ways to manage pandemics.

Combating Future Pandemics Without Lockdowns

Real viruses need to reproduce to be harmful but they can't reproduce alone; they must hijack the manufacturing machinery of host cells. The virus breaks into the host cell and deposits the instructions for the cell to make clones of the virus. A synthetic virus must go through a similar process to fool the host's body into thinking has been invaded by a pathogen. Both synthetic real viruses trigger the same immune response in our bodies. 

The breakthrough that enabled the Moderna and Pfizer synthetic vaccines to work without stripping parts from real viruses was the ability to synthesize the messenger RNA (mRNA) of the SARS-CoV-2 and embed it into the host cell. The mRNA is the set of instructions that tells a cell how to manufacture the protein that triggers an immune response. An immune response is triggered by antigens which in turn causes your immune system to produce antibodies that block or destroy the target pathogen.

James Swartz at Stanford University wants to speed up the process between identifying a pathogen and annihilating it. He imagines building an inventory of bioparticles (empty antigen containers) waiting to be loaded with the specific antigens needed to target the dangerous virus.   As soon as the effective antigens are identified they would be loaded into the bioparticles and the synthetic vaccine could be ready to deliver billions of injections within weeks. In essence, Swartz imagines a biological equivalent of a 3D printer that sits waiting for the right materials and instructions to produce the final product.

Swartz's most formidable obstacle is acquiring the $40 million to develop the concept and test it in humans and another $250 million to create the supp[y chain that would put it into practice. However, this is a trivial amount compared to the U.S. federal government spending over $5 trillion to manage the COVID-19 pandemic and mitigate its collateral problems. That amount of money would fund 20,000 research projects of the magnitude equal to the one proposed by Swartz.

The current pandemic underscored the need to shift from high volume specialized manufacturing processes to more flexible and adaptable production of vaccines; potential pandemics must be stopped before large segments of the population are infected. The mRNA-based Pfizer and Moderna vaccines set records in time-to-market by using recently developed single-use technologies. The next step is to accelerate the processes needed to go from discovering a virus to obliterating it. 

A number of fundraising efforts to promote rapid effective responses to future pandemics are in progress. For example, the Coalition for Epidemic Preparedness Innovations (CEPI) is seeking $3.5 billion to create a platform to have a vaccine ready to combat the next potential pandemic within 100 days of its discovery. The Bill and Melinda Gates Foundation has contributed to CEPI.

Hunting for Novel Viruses

Novel viruses appear regularly yet remain relatively harmless. Most novel viruses originate in other animals and adapt to the ability to reproduce in human cells. For example, novel influenza viruses included avian flu and swine flu. The SARS-CoV-2 and SARS-CoV are coronaviruses that originated in bats and MERS appears to have originated in bats and passed through camels to humans (80% of reported cases in humans occurred in Saudi Arabia). We could prevent or stall the next pandemic by discovering viruses in animals that might jump to humans. This requires large-scale capabilities to find and monitor viruses that have the potential to jump to and proliferate in humans. The knowledge and technology to do so are developing rapidly.

Edward Holmes at Sydney University sampled urine, saliva, and feces of bats in a small area and found 24 new coronaviruses, four of which were closely related to COVID-19. The challenge, then, is to better understand “spillover” (a term scientists use to describe viruses jumping from animals to humans) and respond to the next pandemic before humans begin to spread the disease on a large scale. This underscores the need to expand our ability to use genomic surveillance in both animal and human sources of contagious viruses. 

Genomic surveillance scans genomes to find sequences of interest. The virus (SARS-CoV-2) that causes the disease COVID-19 existed in nature in the form of virus “assembly instructions,” a genome that contains about 30,000 letters each representing one of four chemical compounds (labeled c, u, g, a). The sequence of letters encodes all the information needed to build a virus coronavirus. The SARS-CoV-2 contains a small sequence of just 12 ominous letters (ccu cgg cgg gca) that cost the lives of nearly 3 million people to date. Hunting viruses requires finding such harmful segments in virus genomes. Had those letters been discovered when the COVID-19 first appeared and had a real-time mitigation technology existed, there likely would have been no pandemic. Our challenge is to create those real-time capabilities before the next pandemic strikes.

Virus hunters scan sequences of genomes by identifying the 30,000 letters inique to each suspect virus. So far, 700,000 genomes have been sequenced and more are added every day. Virus hunts identified the UK, South African, and Brazilian variants of the coronavirus. 

The UK and South Africa virus hunterswere able to identify the more deadly variants more quickly because of their systematic genomic surveillance. Genome browsers like the one at the University of California, Santa Cruz is providing access to extensive genome data segments of which can be searched with a click similar to Google Chrome. The technology for rapid real-time mutant identification and research exists and is paying dividends today. A "double mutant" variant (two mutations on the same virus) of COVID-19 was just discovered a few days ago in India. This discovery will allow scientists to determine if a double mutation allows the variant to evade one's immune system. These and advancements in virology give us reason to be optimistic that we might never again suffer the magnitude of virus-induced illness,  deaths and social disruption of the past year.