‘Are ‘super viruses’ a concern with widespread usage of vaccines (similar to ‘super bacteria’ resistance to antibiotics, from widespread usage of antibiotics)? Why are the two different?‘
This answer explains
- Differences between drug (antibiotic and antiviral) and vaccine resistance.
- Why super virus is less likely to emerge in response to antiviral vaccine.
- How natural bottlenecks in human-virus dynamic prevail to limit the scope for a super virus.
- How intense artificial selection pressures imposed by unwitting or willful animal husbandry practices in industrial livestock production increase scope for a super virus. The Marek’s disease – Wikipedia (MDV) vaccine in chickens offers an illustrative example.
Differences Between Drug (antibiotic and antiviral) & Vaccine Resistance
Be they antibiotics against bacteria or antivirals against viruses, studies show drug resistance tends to emerge fairly rapidly. OTOH, be their target bacteria or virus, vaccine resistance occurs only rarely and typically takes many more years to emerge (see below from 1).
Note two interesting features of this comparison,
- Vaccines compared in this study are human. Situation could be quite different with veterinary vaccines as this answer shares with the illustrative example of Marek’s disease – Wikipedia (MDV) vaccine in chickens.
- Pertussis, pneumococcal and hepatitis B are human vaccines with documented data on resistance. All three are relatively simple sub-unit vaccines that offer limited numbers of targets. There may be something to the idea that the more complex a vaccine, greater the number of targets it offers the host’s immune system, the more robust and comprehensive the control it elicits, the stronger the capability to not just prevent disease but also infection and transmission.
The authors of this study (1) propose the reason for this difference between drug and vaccine resistance is two-fold,
- Vaccines tend to be given prophylactically to healthy people, before they get the infection, whereas drugs are given therapeutically to an infected person, typically at a time when they harbor large, even enormous, numbers of the disease-causing organism.
- Having already expanded and mutated during the infection’s incubation period, greater their number, greater the chance for mutations in the disease-causing organism. Mutated organisms also likely spread to new hosts even before the index host begins drug treatment.
- In other words, typically the scale is usually already tipped against an antibiotic or antiviral. Indeed, studies show greater their number at the time of Rx, more likely drug resistance (1).
- Being given prophylactically means vaccine-indued immune responses have much greater scope for preventing a disease-causing organism from even gaining a foothold in the first place, let alone be able to expand, mutate and then spread. A difference in kind from drugs in other words.
- Drugs typically target one or few molecules whereas even relatively simple vaccines offer a multitude of targets to the host’s immune system.
- Both TB and HIV specialists learned the hard way that using a single drug almost invariably leads to drug resistance while combination therapy or multiple drugs that target different pathways and use different mechanisms reduces its chances.
- OTOH, vaccines typically offer multiple targets to the immune system. Even a single protein offers multiple epitopes as targets to T and B cells. B cells also undergo Somatic hypermutation – Wikipedia with the help of T cells. Post-vaccination antibody repertoires are thus typically broad and varied, even varying substantially between individuals. That makes it much more difficult for a mutated organism to evade immune responses. What may evade in one person may not in another whereas blanket evasion is very much the norm against a given drug.
Why Super virus Is Less Likely To Emerge In Response to Antiviral Vaccine
Super virus from antiviral vaccine is inherently different from super bacteria that develop in response to excess antibiotic usage in both humans and livestock. Antibiotics act on not just the target organism but also on our and animal microbiota. They also seep into soil and water from effluents from livestock operations and thus can also act on all sorts of environmental bacteria. Scope of antibiotic selection pressure on bacteria is thus enormous. OTOH, an antiviral vaccine, even one given to millions of humans or billions of livestock, is designed to target one single virus or a narrow set of related viruses. Its scope in the form of selection pressure that yields a super virus is thus inherently much more limited.
Whether it could emerge from vaccines requires we first consider what a ‘super virus’ could be. Typically super is prefixed to microorganisms that have acquired frightening new capabilities often as a result of mutations or genetic exchanges, acquisition of virulence genes being case in point for the latter. Such considerations theoretically limit chances of a super virus to either in-kind exchanges, i.e., between similar types of viruses, given some are RNA, others DNA, or mutations.
Having considered what a super virus could entail, its development is a two sides of the same coin issue.
- One side is the capacity of organisms such as viruses and bacteria to replicate so much faster than us, which in turn enables them to adapt much more rapidly to selection pressures such as host immune responses to vaccines for example. Such adaptations however come with inbuilt constraints since bacteria and viruses cannot adapt away from features where the cost-benefit analysis for doing so entails extreme fitness costs such as death. Usually traits such as coat proteins or receptors used to invade cells, such features thus usually end up being durable targets of host immune responses for precisely such reasons. In other words, a mutually reinforcing cycle between virus and host tends towards a detente that limits the potential for a super virus to develop. This side of the coin, the normal human-virus dynamic, limits the chance for a super virus.
- The problem comes from the other side of the coin which consists of intense artificial selection pressures that we humans ourselves unwittingly or willfully foist on viruses that could instigate the development of a super virus.
Let’s consider two examples that help illustrate the two sides of this coin, influenza and MDV, an economically important disease in chickens.
- Natural bottlenecks in influenza-human dynamic limit the scope for a super virus.
- ‘Leaky’ veterinary vaccine such as the MDV vaccine may increase scope for more virulent virus to emerge in chickens.
Natural Bottlenecks in Influenza-Human Dynamic Limit Scope for Super Virus
Influenza as an RNA virus serves as a useful illustrative example where a 2017 review explored how, contrary to the preconception that flu viruses evolve rapidly, they actually evolve quite slowly (see below from 2).
The authors remind that (see below from 2),
‘New antigenic variants of A/H3N2 viruses appear every 3–5 years, whereas new antigenic variants of A/H1N1 and influenza B viruses appear less frequently (2–5 years for A/H3N2 viruses compared with 3–8 years for A/H1N1 and influenza B viruses)12,23–25. Given that seasonal influenza viruses cause epidemics worldwide, infecting hundreds of millions of people each year1, and that each human is likely to be infected multiple times over their lifetime26,27, it is surprising that new antigenic variants appear so infrequently.’
‘Leaky’ Marek’s disease – Wikipedia (MDV) Vaccine May Increase Scope for More Virulent Virus
Efforts to control MDV in commercial chickens represents the other side of the coin in the form of the artificial selection pressure imposed by a ‘leaky vaccine’ often given to the billions upon billions of livestock that many humans now consider their birthright to consume without restraint whenever they want however much they want, a 20th century innovation enabled by industrialization of agriculture and refrigeration.
What does it take to stock supermarket after supermarket across the length and breadth of a vast country like the US for example with an overabundance of neatly packaged, pristine-looking meat, not to mention the prodigious meat consumption at tens of thousands of fast food joints? Overabundance not because such overabundance is essential for human health, far from it, not even solely because it’s convenient, no. Rather, because it’s something that 20th century technology made do-able. The rest of the modern meat-consuming ecosystem and cultural practices that followed flow from what is true of so much of modern life, that technology makes possible the previously unthinkable.
Economic rather than scientific or humane considerations underlie CAFO (Concentrated animal feeding operation – Wikipedia), where livestock are densely packed in substandard, largely unhygienic conditions through their increasingly truncated, miserable lives, coincidentally the same conditions likely to engender the emergence of new, more deadly viruses.
More prone to infections under such living conditions in turn necessitates more invasive measures such as prophylactic vaccines to control them, a human-made selection pressure on an unprecedented global scale on viruses harbored by livestock but that is what it takes to have an overabundance of relatively cheap meat be just a quick drive to the local supermarket in an increasing number of countries. Any surprise then that such conditions could encourage the development and spread of more virulent viruses, some of which might even be harmful to humans (3)?
While most longstanding human vaccines appear to be sterilizing, the same doesn’t appear to be the case with veterinary vaccines (4).
MDV is a frequent viral disease in chickens where it causes tumors and eventually death. Infected birds spread the virus when they shed their feather follicles. After this disease began to impact commercial chicken operations in the 1960s (5, 6), the USDA began a vaccination program with a vaccine that later studies showed was ‘leaky’, protecting the vaccinated chickens from the disease but unable to prevent virus transmission. As the years passed, vaccinated chickens were found to shed increasingly more virulent virus.
A controversial idea first mooted by a mathematical model in 2001 (7) suggested that imperfect vaccines that do not prevent infection but keep hosts alive might help more virulent pathogens to circulate since normally, such virulent organisms would take themselves out of circulation by killing their hosts. In contrast to a sterilizing vaccine, a ‘leaky vaccine’ is one capable of protecting the host while still allowing the transmission of the disease-causing organism. A ‘leaky vaccine’ is thus an imperfect vaccine.
Hypothesizing that the ‘leaky’ vaccine might be implicated in increasing virulence, a 2015 study (4) first infected both vaccinated and unvaccinated chickens with MDV and then mixed these infected chickens with unvaccinated, uninfected chickens.
- Unvaccinated, uninfected chickens exposed to unvaccinated infected chickens did not become sick.
- Unvaccinated, uninfected chickens exposed to vaccinated infected chickens died.
The authors concluded the ‘leaky’ vaccine was somehow implicated in the vaccinated infected chickens transmitting a more virulent MDV to the unvaccinated, uninfected chickens.
Note the authors cannot and did not conclude that vaccination was responsible for virulence increase. Rather they are careful to conclude only what their data could support, that it was sufficient to maintain more pathogenic strains in the chickens they tested (see below from 4),
‘MDV became increasingly virulent over the second half of the 20th century [19 ,21–24 ]. Until the 1950s, strains of MDV circulating on poultry farms caused a mildly paralytic disease, with lesions largely restricted to peripheral nervous tissue. Death was relatively rare. Today, hyperpathogenic strains are present worldwide. These strains induce lymphomas in a wide range of organs and mortality rates of up to 100% in unvaccinated birds. So far as we are aware, no one has been able to isolate non-lethal MDV strains from today’ s commercial (vaccinated) poultry operations [19 ,23 ]. Quite what promoted this viral evolution is unclear. The observation that successively more efficacious vaccines have been overcome by successively more virulent viral strains has prompted many MDV specialists to suggest that vaccination might be a key driver [19–24 ,34–37 ], though identifying the evolutionary pressures involved has proved challenging. There is no evidence in Marek’ s disease that vaccine breakthrough by more virulent strains has anything to do with overcoming strain-specific immunity (e.g., epitope evolution); genetic and immunological comparisons of strains varying in virulence suggest that candidate virulence determinants are associated with host– cell interactions and viral replication, not antigens [19 ]. The imperfect-vaccine hypothesis was suggested as an evolutionary mechanism by which immunization might drive MDV virulence evolution [2 ], but there has been no experimental confirmation. Our data provide that: by enhancing host survival but not preventing viral shedding, MDV vaccination of hens or offspring greatly prolongs the infectious periods of hyperpathogenic strains, and hence the amount of virus they shed into the environment.
Our data do not demonstrate that vaccination was responsible for the evolution of hyperpathogenic strains of MDV, and we may never know for sure why they evolved in the first place. Clearly, many potentially relevant ecological pressures on virulence have changed with the intensification of the poultry industry. For instance, as the industry has expanded, broilers have become a much larger part of the industry, and broiler lifespans have halved with advances in animal genetics and husbandry; all else being equal, this would favour more virulent strains [28 ], so too might greater genetic homogeneity in flocks [38 ] or high-density rearing conditions [13 ], or indeed increased frequencies of maternally derived antibody if natural MDV infections became more common as the industry intensified in the pre-vaccine era (Fig 3 ) [39 ]. But whatever was responsible for the evolution of more virulent strains in the first place (and there may be many causes), our data show that vaccination is sufficient to maintain hyperpathogenic strains in poultry flocks today. By keeping infected birds alive, vaccination substantially enhances the transmission success and hence spread of virus strains too lethal to persist in unvaccinated populations, which would therefore have been removed by natural selection in the pre-vaccine era.’
A bird-specific virus, humans need not fear getting sick from MDV. However, the same is not true for other viruses that livestock such as chickens and pigs harbor. Some bird and swine flu strains can and indeed do infect humans. Flu strains circulating between birds, swine and humans could mix (reassort) in new ways through a process called Antigenic shift – Wikipedia to create entirely new strains against which human immune response might provide little or no protection, creating the specter of frightening new global pandemics. The 2009 flu pandemic – Wikipedia is a recent example of such a phenomenon where bird, swine and human flu viruses appear to have reassorted and then combined with a Eurasian swine flu virus.
That different countries use different disease control measures in livestock adds to such selection pressure. For example, US and Europe cull chickens that get bird flu which stops further evolution of the virus in its tracks while southeast Asian countries use ‘leaky’ vaccines which do not (see below from 8).
“The most-virulent strain of avian influenza now decimating poultry flocks worldwide can kill unvaccinated birds in just under three days,” Read said. The vaccine against avian influenza is a leaky vaccine, according to Read. “In the United States and Europe, the birds that get avian influenza are culled, so no further evolution of the virus is possible,” Read said. “But instead of controlling the disease by culling infected birds, farmers in Southeast Asia use vaccines that leak — so evolution of the avian influenza virus toward greater virulence could happen.”
Given that bird flu can and indeed has jumped to humans, such measures could thus end up adversely impacting human health as well.
1. Kennedy, David A., and Andrew F. Read. “Why does drug resistance readily evolve but vaccine resistance does not?.” Proc. R. Soc. B. Vol. 284. No. 1851. The Royal Society, 2017. http://rspb.royalsocietypublishi…
2. Petrova, Velislava N., and Colin A. Russell. “The evolution of seasonal influenza viruses.” Nature Reviews Microbiology 16.1 (2018): 47.
3. Leibler, Jessica H., et al. “Industrial food animal production and global health risks: exploring the ecosystems and economics of avian influenza.” Ecohealth 6.1 (2009): 58-70. https://www.researchgate.net/pro…
4. Read, Andrew F., et al. “Imperfect vaccination can enhance the transmission of highly virulent pathogens.” PLoS Biology 13.7 (2015): e1002198. http://journals.plos.org/plosbio…
5. Purchase, H. Graham, and E. Fred Schultz. “The economics of marek’s disease control in the United States.” World’s poultry science journal 34.4 (1978): 199-204. https://naldc.nal.usda.gov/naldc…
6. Leaky vaccines could lead to more virulent pathogens | PLOS ECR Community
7. Gandon, Sylvain, et al. “Imperfect vaccines and the evolution of pathogen virulence.” Nature 414.6865 (2001): 751. https://www.era.lib.ed.ac.uk/bit…
8. Some vaccines support evolution of more-virulent viruses