[ed. note: Michael Jorrin is a longtime medical writer (not a doctor), I’ve dubbed him “Doc Gumshoe” for his coverage of medical and health topics for Stock Gumshoe. This piece, like most of Michael’s work, is not specifically investment-related — but for those who think about speculating in the next Zika cure or similar “hot tip” a little background might help]

Last year Ebola was terrifying parts of Africa, with reason, and making lots of us on this side of the Atlantic distinctly uneasy – with, in my view, much less reason. Now the scary virus is Zika, which really is a frightening reality in large parts of Latin America, as well as parts of Africa and Asia, but much less menacing in the US and Canada, and much less in Europe as well. And now we have to worry, at least a little, about MERS (Middle East respiratory syndrome), as well as an assortment of flu viruses. As for the human immunodeficiency virus (HIV), fortunately, in the developed world, it can be controlled reasonably well in most patients. Unfortunately, there are large parts of the world where it continues to rage out of control.

Do we have the impression that new viruses are emerging with increasing frequency, causing more devastation? Well, that’s only if we abandon historical perspective. The influenza pandemic, which started in January of 1918 and lasted nearly three years, infected 500 million people and killed at least 50 million and perhaps as many as 100 million – about 5% of the global population at that time. It was the most deadly epidemic since the bubonic plague in the mid 14th century.

But it does seem to be the case that viral diseases travel more quickly and easily from the location of their initial outbreak to distant parts of the planet. The virus can’t really go anywhere on its own, but the host – the person or animal infected with the virus – can go halfway around the globe in a few hours and transmit the virus to another host. And, because viruses mutate, there is always the fear that a virus which had been previously thought to be a factor only in certain regions might thrive and become a threat in our own vicinity. This fear is not paranoid, but it needs to be tempered by a bit of information about viruses, their carriers, and their hosts.

So, forgive me if you already knew this, but it probably wouldn’t hurt to review what we know about viruses.

What are viruses, and how do they make us sick?

Virus is a Latin word meaning, essentially, a nasty, slimy, evil-smelling, poisonous liquid. The name was first used at the end of the 19th century to describe infectious agents that could not be seen by an optical microscope or trapped in a filter designed to capture bacteria; thus the Latin term seemed to be entirely appropriate. For several decades after it was determined that there were such infectious agents, the term “filterable virus” was frequently applied to them. Pasteur and other 19th century scientists had reasonably good evidence that such agents really did have the capacity to cause infections. No microbe detectable with a microscope seemed to be the cause of rabies, but rabies was clearly transmitted by the bite of an infected animal. The tobacco mosaic spread from plant to plant, yet no agent was visible, nor could any agent be trapped by the filters that caught bacteria.

However, scientists suspected early on that viruses were something more than “liquid life,” as they were sometimes described. In 1915, the following statement appeared in Lancet: “We do not know for certain the nature of an ultra-microscopic virus. It may be a minute bacterium that will only grow on living material, or it may be a tiny amœba which thrives on living micro-organisms. It is quite possible that an ultra-microscopic virus belongs somewhere in this vast field of life more lowly organised than the bacterium or amœba.”

The speculation that a virus was “a minute bacterium” was borne out about 20 years later, when, with the development of the electron microscope, it became possible actually to see that viruses were discrete individual particles and not a liquid life form. It was just that they were so much smaller than the smallest previously observed micro-organisms that they could not be seen through optical microscopes. As to what they actually were, the investigation was just beginning, and would not really produce significant results until the second part of the 20th century.

How much smaller than bacteria are viruses? Their size is calculated in nanometers (nm), generally between about 20 nm and 300 nm, whereas bacterial size is calculated in micrometers (μm). A nanometer is a billionth of a meter, while a micrometer is a millionth of a meter – a thousand times larger. So, in general we can say that bacteria are a few hundred to a thousand times bigger than viruses.

Viruses are not cells. They are composed of two or at most three parts – a core consisting of RNA or DNA, a capsid or capsule around that core, consisting of proteins, and in some viruses, a coating or envelope consisting of a simple lipid. Viruses depend for their existence and function on host cells, whether the cells are in animals or in plants. Once they enter the host cells, they are able to reproduce.

While cells of any kind, human or otherwise, reproduce by cell division, viruses copy their genetic material inside the host cell. Once they attach to a host cell, they penetrate the cell wall, move inside, shed their outer layers, and kidnap the host cell’s resources to copy their RNA or DNA. The newly-formed virus cores then construct protein capsids around the cores. If it is a lipid envelope virus, it also forms that part of its anatomy, all of this stealing the host cell’s resources. This process usually kills the host cell. The virus then emerges into the intracellular space, attaches itself to another host cell, and continues the process of reproduction.

Whether viruses are alive or not is a matter of some dispute, although from my point of view that dispute should be left to philosophers and theologians. It seems clear to me that viruses are indeed alive. Why else would they go through all the steps described in the paragraph above if not to be fruitful and multiply? Sounds like life to me.

But viruses need transportation to get to the hosts

Viruses are hitchhikers. They have no means of locomotion. But they do manage to get from one host to another with great success. For example, if you have a cold, when you cough or sneeze, you are propelling a huge number of virions (that’s the name for an individual virus particle) into the air in your immediate proximity. If someone is in the space into which you discharged your viral explosion, that person may inhale some of those virions and become infected. In any case, a portion of that viral load will settle on a surface somewhere – a surface that someone else may touch. Then that person has virus on his or her hands, from whence the virus may find a way to enter that person’s body.

Viruses don’t survive for long on their own, outside of host cells. The survival time depends on the type of virus and on the environment. They tend to survive longer on hard, non-porous surfaces, like glass or stainless steel; however, they fairly quickly lose their capacity to infect another host. Some viruses, like the rhinoviruses, which cause colds, may be able to cause infection for as long as 24 hours after being deposited on a hard surface, but for a much shorter time on porous surfaces or on the hands – usually not more than about one hour. Flu viruses, fortunately, have an even shorter survival time on porous surfaces and hands, in the neighborhood of 15 minutes. This is not true of parainfluenza viruses, which can survive considerably longer – up to four hours on porous surfaces.

However – and this is a big however – the aerosols that we emit when we cough or sneeze tends to hang in the air, and any virus present in those tiny droplets can remain infectious for several hours, especially in cold weather.

Aerosols are just one mode of transport for viruses. Blood-sucking insects are another, especially mosquitoes. Fortunately, not every type of mosquito is a vector for every virus; if that were so, our species would be in sorry straits. (Vector is the formal term for virus carriers, but it is somewhat confusing, because “viral vectors” is the term used by molecular biologists for the means used to convey genetic material into cells in the process of genetic manipulation, so I am going to stick with 
“carrier.”) For example, Zika, the virus that is most in the news these days, is primarily transmitted by a mosquito labeled Aedes aegypti, although several other species of the Aedes genus can also act as carriers for Zika. Aedes aegypti and other Aedes species also transmit such diseases as  dengue fever, yellow fever, West Nile fever, chikungunya, and eastern equine encephalitis. And Zika has been found in other mosquito genera, including Anopheles and Culex, although there is no evidence that these mosquitoes are able to transmit the virus to other hosts – at least, so far.

A scenario that epidemiologists don’t like to talk about is this: large numbers of individuals infected with Zika come to an area where there are no Aedes mosquitoes. These unfortunate persons are then bitten by the local mosquitoes. In most cases, those other mosquitoes do not transmit the viral infection. But there is no intrinsic reason that the virus or the local mosquitoes, or both, could not adapt, such that the hordes of mosquitoes that torment summer visitors to Alaska, for example, might not someday become carriers of Zika, or of some other mosquito-borne virus. How likely is it? I would guess, not very – but not impossible.

And then there are other modes of transmission. Ebola, as we know, is transmitted in bodily fluids, which include saliva, perspiration, and other less mentionable substances, such that physical contact of any kind with an infected person imposes a high risk of acquiring the infection. HIV is also transmitted in bodily fluids, but the number of bodily fluids that can act as HIV carriers is quite small, limited to blood and semen. If HIV could be transmitted through aerosols, mosquito bites, or other bodily fluids, a lot of us would be dead by now.

Why are some viruses more “successful” than others?

That difference between Ebola and HIV points to a highly important factor relating to the “success” of a viral strain. HIV is a highly successful virus. It is estimated by the World Health Organization that HIV has resulted in the deaths of about 25 million people worldwide since the disease was first reported back in the 1980s. Nearly 40 million are currently infected. From the viral perspective (if viruses can be said to have a perspective), killing their victims is not a mark of success. What the viruses “want” to do is keep their victims alive so that they can transmit the infection to other unfortunates. HIV is exceedingly good at doing exactly that. A person can be infected with HIV for a long time, sometimes years, and not know that he or she is infected. And then, for a long, long time, they can survive with their disease, a potential source of infection to others with whom they might have sexual encounters or engage in practices such as recreational narcotics with a shared hypodermic needle. From the virus’s point of view, this is dandy. There is a huge viral reservoir out there, and the probability is that it isn’t going away, despite efforts to control it.

In contrast with the HIV pandemic, which has lasted more than 35 years and is still going strong, the Ebola epidemic killed 11,315 people, almost all in Liberia, Sierra Leone, and Guinea, and lasted about 21 months. That epidemic has been officially declared as finished by WHO. In comparison with HIV, Ebola was a flash in the pan – sudden, intense, dazzlingly terrifying, but not in the same category as HIV. (This, by the way, is not to say that Ebola won’t be back to scare us once again.)

Why is this? Essentially, because Ebola infects and kills its victims very quickly, and very noticeably. It is not a subtle malefactor like HIV. Symptoms emerge right away, and once the populace knows about the symptoms and the risk of the disease, the need for containment and isolation becomes apparent. Currently, if there is a major reservoir of Ebola out there, it is not in humans, but in other animal species.

What is the effect of vaccination on the survival of a virus?

When we get vaccinated or get our kids vaccinated, what we’re mostly thinking about is protection of the individual from the disease. But vaccination does something else which may be even more important than protecting the individual. An effective vaccination program can essentially wipe out, eliminate, exterminate, the virus itself.

Consider smallpox. This truly dreadful infection has been one of the greatest killers of humans in history, and smallpox continued its killing spree throughout most of the 20th century. Smallpox is estimated to have caused the deaths of 300 to 500 million people during the 20th century; in 1967 alone, smallpox caused 2 million deaths. But the last naturally-occurring case of smallpox occurred in Somalia in 1977. One laboratory worker was accidentally infected in 1978, and in 1980 the World Health Organization pronounced that smallpox had been eradicated.

How did this happen? I would point to two crucial factors. One is that smallpox has only one host – we humans. Animals are not affected by smallpox. Cattle get cowpox, and it is from cowpox that the smallpox vaccine was originally developed. Cowpox is related to other viruses in the vaccinia family (vaccinia, from vacca – the Latin word for “cow”), and it is from cowpox that the smallpox vaccine was developed by Edward Jenner at the very end of the 18th century. And because we’re the single smallpox host, and there are no animal reservoirs, an effective vaccination program could – and did! – stop the virus by eliminating the viral reservoirs. So it’s not just that the individual humans are protected from the disease, it’s that the virus has no place to hide.

As a child in Cuba, where I was born and lived until I was eight years old, there was no question whatever that I would receive my smallpox vaccination. I got inoculated with the vaccine on my left calf, and within a few days a really nasty, runny sore appeared, meaning that the vaccine “took.” In Cuba in those years, one saw quite a number of people with pockmarked faces – smallpox survivors. I had learned what those pockmarked faces meant, and having this sore on my leg was a small price to pay for preventing that disease. But no child today gets a smallpox vaccination. Victory over that disease, at least, has been achieved.

In a certain sense, that particular victory was not just the result of a large, well-conducted, concerted global effort. It was also partly a matter of luck. We are lucky that the smallpox vaccine is highly effective, and that it lasts a long time. And we are lucky that the smallpox virus itself has not changed – it did not mutate its way around the vaccine, as some other viruses do.

Flu viruses, in contrast, are devious. They mutate constantly, even during the course of a single season. The vaccine that may to some degree be effective this season would be likely to be much less effective next season. Unlike the smallpox vaccine, the flu vaccine needs to be reformulated annually. And we need to be revaccinated annually, in order to maintain some degree of resistance to the current dominant flu strains.

All of this is common knowledge. People are aware that the flu vaccine is short of totally effective, and that some years the CDC gets it wrong and fails to identify the next season’s chief malefactor. And also, that year after year they have to go through the same business of “getting their flu shot,” with the same sore lump in their upper arm, the same possibility of feeling lousy for a day or so, and no guarantee that they won’t get the flu anyway. It’s no wonder that flu vaccination rates are so low – the rate for children has been slowly trending upward, but it’s still only about 60%, while the rates for adults, i.e., over the age of 18, have been hovering around 40%. The highest rate is for persons over the age of 65, who presumably are aware that they are at a higher risk if they do become infected with flu. But that rate is only about 67%.

However, even with those lousy vaccination rates, the flu vaccination program is having real effects. One of the trends that epidemiologists have been remarking is that even when the flu vaccine misses the mark, or when a new viral strain appears, the disease episodes are not nearly as severe as might have been anticipated. The 2013 flu season focused attention on a variant labeled H3N2, especially on some patients who apparently attracted the virus from contact with pigs. Similarly, in 2009 the villain was H1N1, dubbed “swine flu.” In spite of the spotty effectiveness of the vaccine in those years, the flu was not nearly as bad as it had been in past seasons.

There appear to be two reasons for this, neither generally recognized by the public at large. One is that even when the current flu vaccine is not precisely spot on, it is at least to some degree effective. A person who is vaccinated and becomes infected with a flu strain that is not specifically targeted in the current vaccine is likely to have much less severe flu symptoms than an unvaccinated person. The vaccine may not prevent infection, but it makes the symptoms less severe.

Another effect has to do with “herd immunity,” the effect that essentially wiped out the smallpox virus. With flu, the way it works is this: year after year, the CDC attempts to predict the most prevalent and the most dangerous flu strains for the coming season, and to formulate a vaccine that targets either three strains (trivalent vaccines) or four strains (quadrivalent vaccines). Even with poor vaccination rates, this results in a degree of herd immunity. The result is that the viral strains most likely to form a reservoir in the human community are therefore the ones not targeted by the vaccine – the ones that causes less severe infections. So, yes, people get the flu. But it’s not as bad as it used to be.

I know lots of people, including good friends, who refuse to get a flu shot. I do not lecture them or badger them. But if any of them should happen to read this, I will only mildly observe that they are behaving in a way that damages herd immunity. They are perhaps not as guilty as the parents who refuse to get their kids inoculated against measles, mumps, and rubella. Those parents may have finally rejected the nonsense about the MMR shots and autism, but they look around and see that hardly any kids get those illnesses anymore, so why bother getting their kids vaccinated? The upshot is that herd immunity is seriously compromised, and we get a measles epidemic like the one that sprouted in California in 2014.

That outbreak, which resulted in about 230 cases of measles, was thought to have originated in some school populations where only about half of the kids were immunized. In comparison with epidemics that infect and kill millions, a local measles epidemic with 230 victims doesn’t sound all that terrible. But it needs to be seen in context: measles had been declared eliminated in the United States as of the year 2000; the only cases of measles were thought to have been acquired abroad. The refusal of some parents, for whatever reason, to immunize their children shredded herd immunity. And it wasn’t only the unvaccinated kids that got sick. Because MMR shots are not 100% effective, some kids got measles despite having received the shots. If all the kids with whom they came into contact had been vaccinated, the chances that these kids would have been infected with measles would have been close to zero. What protects all of us is our own resistance to infection combined with the absence of a reservoir for the pathogens – herd immunity.

What does it take to develop a vaccine?

Back in the 18th century, there was nothing to stop Edward Jenner from inoculating people with cowpox to see if that would prevent them from being infected with smallpox. These days, that would never fly. Before we experiment with a vaccine – or a drug, for that matter – in humans, we must first test it in an animal. But the animal has got to be susceptible to the infection that we’re trying to prevent by means of a vaccine. Currently, the animal of choice is usually a mouse. Mice are subject to many of the same diseases as humans, including cancer, diabetes, hypertension, and lots of infectious diseases. If a suitable mouse can‘t be found, a strategy that is being increasingly employed is to tinker with the mouse’s genome and create a genetically-altered mouse model that is susceptible to the particular infection. And since mice start reproducing at the age of about a month, it’s possible to breed quite a lot of mice in a relatively short time.

Developing a vaccine should, in theory, be straightforward. This does not mean it should be easy or quick. What a vaccine does is alert the human immune response to a possible threat. The vaccine tells our immune mediators, “Here’s what the enemy looks like. If you ever spot any of these guys invading your precincts, go after them and wipe them out.”

In the case of the smallpox virus, it was exceedingly fortunate that there was sufficient similarity between the cowpox virus (vaccinia) and the smallpox virus (variola) that inoculating people with vaccinia permitted the immune system to recognize and eliminate the variola virus. That was a rare lucky break, especially since those 18th century scientists knew nothing about the immune system and nothing about viruses. All they knew was that people (mostly women who milked cows, or “milkmaids”) who had experienced cowpox infections didn’t get smallpox.

Even without any real understanding of the immune system, observers knew that people who had survived some diseases such as smallpox did not succumb to that disease again. They were immune. By the last years of the 19th century, scientists were beginning to explore the concept of acquired immunity as a way of guarding against disease. It had been observed that in a herd of cattle in which some animals had died of anthrax, some of the survivors appeared thereafter to be immune from anthrax. Was it possible that inducing a mild infection with a pathogen could result in immunity from that pathogen in the future?

It turns out that not even a mild infection is necessary. It is often enough just to provide a means for the immune system to recognize the virus. The immune system employs a phalanx of agents that fight off viruses. Immunoglobulins of two types, IgM and IgG, are rapidly produced as soon as the cells of the immune system recognize the viral invader. They attack quickly, but not always quickly enough to prevent the host (human or animal) from getting sick. The IgM is only present while the system is actively attacking the virus, but IgG hangs around indefinitely and prevents the virus from gaining a toehold. This type of immunity is called humoral immunity.

Another class of protective agents are the T-cells, which scout around and look for viral fragments on the surface of cells in the host’s body. When they locate a cell that shows evidence that it has been invaded by virus, killer T-cells are recruited to destroy the cells that have been invaded and thus stop viral replication in those cells. As it happens, HIV specifically targets T-cells, which makes this kind of defense much less effective against HIV.

There are several means of informing the immune system about the characteristics of viruses to be on the alert for. One obvious means is the virus itself, either killed or weakened – “attenuated” – to make it unlikely to cause disease. In some cases, it must be acknowledged that persons whose immune system is debilitated may develop an illness when inoculated with attenuated live virus, but for most of us, this form of vaccination is quite safe and highly effective. Another option is to employ only those markers on the surface of the virus as the signal to the immune system, so that the actively-replicating elements of the virus are not delivered as part of the vaccine. Similarly, it is sometimes possible to use only specific viral proteins as vaccines, also avoiding the risk of transmitting the full-blown disease along with the vaccine.

A bit of good news on the Zika front is that a vaccine for dengue has recently performed quite well in a small study in human volunteers. Dengue is part of the same family as Zika, and the techniques used to develop the dengue vaccine may work for a Zika vaccine as well. Both dengue and Zika are transmitted by the same mosquito, Aedes aegypti. Dengue is currently the most common mosquito-transmitted disease in the world, infecting about 400 million people world-wide. Fortunately (as with Zika) most recover and are immune to the specific dengue serotype they were infected with; however, if they should happen to be infected with a different dengue serotype, they may develop serious and potentially fatal hemorrhagic fevers.

When a likely candidate for a Zika vaccine is developed, it will be necessary to conduct extensive tests in animals – usually mice – before risking a human trial, and, as I pointed out earlier in this piece, the mice need to be susceptible to the specific virus. One mouse variety has indeed been found to be susceptible to the Zika virus, opening an essential pathway to the development of a vaccine. These mice, designated AG129, lack the interferon alpha receptor, which renders them immunodeficient. Within six days of being inoculated with the Zika virus, the AG129 mice showed signs of neurologic disease. Infected mice became lethargic, lost weight, and died. Elevated levels of Zika were found in the brains and reproductive organs of these mice, not unlike the effects of Zika in humans. Mice in a control group that retained the interferon alpha receptor had high levels of the virus in their systems, but showed no symptoms. The success of the dengue vaccine and the Zika-susceptible mouse model add up to a distinct glimmer of hope.

But what about drugs that attack the virus once we’re infected?

Antibiotics have no effect on viruses. The basic reason for this is that in comparison with the microbes that are the targets of antibiotics, viruses are much, much smaller. Bacteria and related pathogens are as much as one thousand times larger than viruses. The antibiotics, which are typically fairly large molecules, literally cannot find the tiny viruses. Another, and perhaps equally fundamental reason, is that many antibiotics are derived from naturally-occurring substances that were developed in life-forms as a way of fending off attacks by bacteria. These antibiotics target weak points in the bacterial armor, and they may be considered part of an evolutionary process in the continuing competition between bacteria and their prey.

Antibiotics’ total lack of efficacy against viruses hasn’t prevented lots of doctors from prescribing antibiotics for kids – and even adults – with viral illnesses, on the grounds that the antibiotic might prevent a secondary bacterial infection. This prescribing practice has been condemned many times, especially because it can easily foster the emergence of resistant strains of common bacterial pathogens. I underscore this point because lots of people might misunderstand the main point. It’s not that antibiotics are less effective against viruses, or that, as in the case of kids with colds, the kids mostly get better on their own, so there’s no need for antibiotics. The main point, which I will repeat once more at the risk of being truly tedious, is that when aimed at viruses, antibiotics miss by a mile, but their use risks significant collateral damage.

The drugs used against existing viral infection are relatively new additions to the so-called pharmaceutical armamentarium. None were in use until the mid-1970s, when arabinosyl adenine (ara-C) was first used to treat varicella zoster and herpes simplex. Ara-C had major limitations and was not in wide use for very long, supplanted by acyclovir (Zovirax or Valtrex). Since then, the development of new agents for the treatment of viral infections has been a continuing series of victories. Hepatitis C is now a curable disease. People with HIV, if they are lucky enough to live in a part of the world where treatment is widely available, can lead relatively normal lives and can anticipate a relatively normal life-span. As for herpes, which for some people had been a kind of curse, that curse has been mitigated.

Research and innovation in treating viruses continues to move forward, presenting great benefits for patients and huge opportunities for pharmaceutical outfits. Having run on quite long enough in this installment, I will devote more space to surveying new developments in this area in an upcoming Doc Gumshoe piece.

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One small addendum: we’ve been reading about the possibility of eliminating the Zika virus by releasing huge numbers of sterile male Aedes mosquitoes, which would mate with the females (the ones that actually do the biting), resulting in zero offspring and the eventual disappearance of the species. A nice idea, except that those Aedes guys don’t range any further than about a quarter of a mile from where they hatched, meaning that to exterminate the whole species would require blanketing the entire tropics with those artificially sterilized buggers. Same thing goes for gene-editing to create an Aedes species that is not a vector for Zika. As science, it’s a highly interesting idea. As a way of eliminating Zika, I doubt it.