A long history of human epidemics

The present pandemic is unprecedented in recent history, it will surely upend economic stability, and cause great hardship for many of the most vulnerable of the world’s population. But it is really only the most recent in a long history of such epidemics that have plagued mankind for millennia.

My prediction is that like most every other epidemic disease that has entered the human population, this one is not going away, probably ever. At least that has been the pattern throughout the long history of introduced diseases—they start as epidemics and pandemics and, short of a world-wide vaccination assault, remain as “childhood diseases”, meaning, everyone contracts the disease as a susceptible child, and either dies or retains immunity as an adult.

What I find fascinating is that these epidemics were inevitable given our ability and will to dominate and populate the entire earth. It is another way that we human beings are exceptional—in addition to be extraordinarily smart (or maybe too clever by half), we are disease-laden.

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Short history. This pattern of disease started with domestication of plants and animals, several thousand years ago. With a stable source of food, people became situated and eventually aggregated in towns and cities, and tending their flocks and herds, sampled all of the bacteria and viruses from birds, pigs, cows, sheep, and horses—efficiency living, cheek to jowl. Germs and germ-theory were unknown. Toilets were not sanitized because there were no toilets, and nonetheless, poop happens. Multiple generations living in close quarters tend to share everything, including respiratory effluvia.

Introducing a new infectious agent (let me just focus on viruses, although similar principles apply to bacteria and other infectious agents) into such a population that has never before seen the disease is known as a “virgin soil epidemic”. Weird word usage, but it means that everyone is susceptible to an infectious agent. The virus found in such an epidemic would be the one able to spread most rapidly within a population. If the virus is too virulent (nasty), it kills its host before it can be transmitted. If it doesn’t replicate well in human beings, it cannot be effectively transmitted (virus numbers too low). In a high-density population where everyone is susceptible and spread is via casual contact, an infectious agent can be highly virulent, even deadly, and still find a new host before its previous host succumbs. On the other hand, if it kills its host before it can be transmitted effectively, it fades out of the population. An example of this is Ebola virus. It is extremely lethal but requires pretty intimate contact so that, prior to 2014, it periodically broke out and infected about 300 people and then faded away. Each outbreak probably involved a new human-animal interaction (and we think the origin species is the fruitbat, but it has also found its way into non-human primates that can hunted and sold as bushmeat). Ebola virus has now evolved to be somewhat more infectious, and thus recent epidemics include thousands of people.

On the other hand, if an infectious agent lands in a low-density population or a population in which most people are already immune, the chances that it finds a new host goes down, and the only viruses that can persist are those that keep their host alive for a long time or actually remain with the host forever (herpes viruses are co-speciated with all virtually all vertebrate species). So that’s why the predecessors of our agrarian ancestors did not have these massive viral epidemics: small, dispersed bands of hunter gatherers could not have sustained virulent epidemic diseases. If one landed in a community, it would kill a few members of the group, and then fade away as it would lack new susceptible hosts.

So, sometimes, although it is unpredictable, an infectious agent from an animal is able to cross over and infect human beings, and this is known as a zoonosis. In the high-density human communities, highly virulent diseases took hold and remained within the population for centuries. This is what happened with the introduction of smallpox, measles, mumps, rubella, diphtheria, pertussis etc. and it is what continually occurs for influenza A and B (a special case reserved for another lecture). These diseases entered the human population only after: 1) our population density increased such that they could be rapidly transmitted; and 2) the size of our communities increased so that there was always a source of new-born susceptible hosts (e. g., measles requires an interacting population of 200,000-500,000 people). Thus, we have childhood diseases (to extend this idea, think about the consequences of introducing ALL of the diseases that arose in Europe and Asia into the huge, naïve populations present in the Americas and Polynesia in the 15th and 16th centuries).

Such infections can be mild or lethal, we have no way of predicting, but the ones we notice cause serious disease. Influenza is a bird virus, usually does not cause disease in birds, but causes death in human beings, or at least makes people WANT to die. SIV causes some morbidity in chimpanzees, but as HIV in human beings, it is almost always fatal (without anti-viral drug therapy). Rabies is found in healthy bats, and it is 100% fatal in people (without early vaccination). Hantavirus is found in wild mice, and causes death in humans, etc.

The take-home message is that “crowd epidemic disease”, is an inevitable consequence of suddenly altering our human ecosystem from that of sparse groups of hunter-gatherers to high-density communities. Add in the continuous sampling of viruses from all the world’s wild animals, along with the invasion and disruption of tropical forests, and voilà, you have human beings, the most diseased species on earth.

21st century. Four coronaviruses account for a substantial percentage of what we experience as seasonal common colds. The present COVID-19 pandemic is caused by a novel coronavirus (SARS-CoV-2) that comes from bats, for sure. Whether it found its way into the live Chinese meat markets via an intermediate host is unknown. This is the 7th coronavirus to be found in the human population, and it is 80% identical to SARS-Cov-1, the agent responsible for the 2003 SARS epidemic (also from bats) and 96% identical to a recently identified bat coronavirus.

The SARS-Cov-1 virus originated in horseshoe bats and somehow infected masked palm civets, the latter a delicacy in southern China. Until the present epidemic, wild animals, from snakes to civets were available at a wet market that appears to be the origin of the present epidemic. A study from 2017 in which Chinese researchers sampled viruses from a cave of horseshoe bats found many variants of bat coronaviruses, some of which could grow in human cells. It was only a matter of time before one of these viruses, again caused a human epidemic. Slaughtering and eating wild animals, especially now that we know these animals can be contaminated by virus-harboring bats, risks starting an epidemic. It’s like having unprotected sex with multiple concurrent partners some of whom are i.v. drug users. Yea, it’s an infectious virus, but you’re askin’ for it. The Chinese government officially closed these markets for a time, although I would not count on this being the last we hear of wet markets in China. Should we demonize China for starting this pandemic, well no, and we certainly should not blame Chinese people, but on this one very narrow issue the administration has a point. The pandemic was caused by highly risky cultural practices that made another epidemic inevitable. Note that there are examples the world over of human practices that make zoonotic infections likely, this is not limited to China.

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COVID-19. The SARS-Cov-1 virus epidemic was contained by isolation and quarantine. Since 2004 there have been no known cases of SARS-Cov-1. It may be too virulent, as it killed or incapacitated its host at a rate of about 15%. It also may have manifested symptoms before becoming contagious, and there may have been fewer asymptomatic cases. It might have faded out of the population eventually unless it evolved to be less virulent or transmitted more frequently. I don’t know. SARS-CoV-2 is unfortunately much better suited to epidemic spread and even maintenance in the human population. It seems to have an incubation period of about 4 days before the onset of symptoms and a long infectious period that includes 10 days before need for hospitalization. The total time that a patient is contagious it is probably long, variable and not well characterized. The time between onset of symptoms and death ranges from 2-8 weeks. But lethality is less than that of SARS-Cov-1 at between 1-3% (although this figure is an estimate because we do not know the real number of total infections). Importantly, it appears to be often asymptomatic in young people who are nonetheless contagious.

The near future. My guess is that there is little possibility that this virus will fade out of the human population without the widespread use of an effective vaccine followed by testing and targeted “ring vaccination” (vaccinating everyone in proximity to a new outbreak as was practiced for the elimination of smallpox). I hope I’m wrong, but as the virus has already found its way all over the earth, it may remain simmering in the population with the potential to break out at any time. Our present measures of isolation and quarantine have “flattened the curve”, that is limit the prevalence of disease at any one time in order not to overwhelm the medical system, but, unlike SARS-Cov-1, we will not be able to contain it by isolation and quarantine. As I write this, the U.S. is leading the world in confirmed cases of SARS-CoV-2 infections, but testing in many other regions of the world is lacking. Based on the patterns exhibited so far, this virus is likely to ravage high density populations wherever they exist, especially those in which there is multigenerational cohabitation. We can only hope, without much confidence, that the virus does not gain access to the dense cities of Africa and the Indian sub-continent. My guess is that we will not be able to safely return to a pre-COVID existence until the incidence (new cases) for an isolated region approaches zero. I suggest that state and national isolation policy should be informed by a close analysis of incidence.

There is reason to be optimistic that we can develop a safe and effective vaccine, but it is not trivial, we have yet to make an effective, sterilizing vaccine to any coronavirus. The blood from infected patients contains effective, neutralizing antibodies, that is, antibodies that can bind to the virus and prevent it from infecting a human cell, but recent studies reveal that many people do not have high levels of these antibodies. This shows the potential for human immunity if the right vaccine can be developed, but there should be notes of caution. Immunity to the mild, cold-inducing coronaviruses is thought to be short-lived, though I have not found a study that confirms this. However, even a window of immunity might be sufficient to break the chain of SARS-CoV-2 transmission and curtail the present epidemic. We should also be aware that there are instances when new vaccines work well in pre-clinical models, but actually cause problems in human beings. More troublesome, in pre-clinical vaccine trials using attenuated live SARS-CoV-1 virus, there were reports of lung and liver damage. In addition, sometimes, antibodies actually make a person MORE sensitive to a virus. A vaccine developed to elicit immunity to respiratory syncytial virus (RSV) in the 1960’s actually caused deaths in subsequently exposed children. The immune system pursues a “type II” response post-vaccination, and when confronted with the actual infectious virus produces an ineffective, or even deleterious immune response. In addition, there is the possibility of antigen-dependent enhancement (ADE). We see this played out naturally with Dengue Fever; if you are infected by one virus strain, you make antibodies that put you in real danger if exposed to one of the other three Dengue virus strains. There was some evidence for ADE in studies on a vaccine against the SARS-Cov-1 virus. There are at least 100 on-going projects to create a vaccine using old and new technologies, and my bet is that there will be successes—especially if we practice safeguards to prevent vaccine-related adverse events.

More new epidemics. We have not seen the end of new or re-emerging diseases. In the past few decades we have seen the emergence of HIV infections, SARS, MERS, Lyme disease, Escherichia coli O157:H7 (E. coli), hantavirus, dengue fever, West Nile virus, Chikungunya virus and Zika virus. So, in addition to this new SARS-CoV-2 virus, there are many more zoonotic agents that could potentially cause an epidemic. I would like to end by describing a concept that is perhaps not widely understood. As human beings, we are not only culturally or genetically connected through a common ancestry. We human beings are biologically connected in the present through our exchange of infectious agents and our common susceptibility to disease. Perhaps it has taken a world-wide pandemic to show us that borders are illusionary, we are of one species on planet earth.

Stephen M. Hedrick

Distinguished Professor

UC San Diego

shedrick@ucsd.edu

Stephen Hedrick

Dr. Hedrick is a distinguished professor at University of California, San Diego. His research focuses on homeostatic regulation in lymphocyte populations. He aims to understand the regulators of areas such as survival and quiescence, expansion and survival, and alternate forms of programmed cell death.

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