Information

Can disease resistance from vaccination be inherited?

Can disease resistance from vaccination be inherited?


We are searching data for your request:

Forums and discussions:
Manuals and reference books:
Data from registers:
Wait the end of the search in all databases.
Upon completion, a link will appear to access the found materials.

If a person has taken a vaccine against a particular disease and is resistant to that disease, will his/her children will be resistant to that disease??


Not usually. I say usually because there's a fairly new (~15 years old) branch of genetics known as epigentics which has been shown to allow for inheritance of acquired traits. So it's possible that if the way in which a vaccine worked was altering your epigenome or genome, that it could be passed down to your children. However, that's just a hypothetical since none of the vaccines that I know of currently work in that way, but maybe something in the future will.

As of now, vaccines generally give you immunity by introducing some portion of the virus you're vaccinating against and "sensitizing" your immune system against it. This could be the viral envelope, it could be viral DNA/RNA, could be a viral protein, etc. However, in all of these cases, your immune cells are carrying out a fairly complex process in which they make antibodies with an almost random pattern constantly, and when one is produced that binds to this virus, it tells the B cell that produced that antibody to start making more. In this way, it "confirms" that this B cell is onto something.

Having said that, the B cells themselves are not passed on from parent to child, so a child would not be permanently immune to a virus even if the parent was. BUT, some antibodies can be passed from mother to child through the umbilical cord. These antibodies have a finite life and since they're not cells, they don't replicate and device. So the child would be immune to whatever a given antibody works against as long as that antibody remains in their system (usually on the order of weeks to months). Once the antibody is degraded, they no longer have any immunity, just as their parents did not have immunity before being vaccinated.


Gene Targeting

Although classical methods of studying the function of genes began with a given phenotype and determined the genetic basis of that phenotype, modern techniques allow researchers to start at the DNA sequence level and ask: “What does this gene or DNA element do?” This technique, called reverse genetics, has resulted in reversing the classic genetic methodology. This method would be similar to damaging a body part to determine its function. An insect that loses a wing cannot fly, which means that the function of the wing is flight. The classical genetic method would compare insects that cannot fly with insects that can fly, and observe that the non-flying insects have lost wings. Similarly, mutating or deleting genes provides researchers with clues about gene function. The methods used to disable gene function are collectively called gene targeting. Gene targeting is the use of recombinant DNA vectors to alter the expression of a particular gene, either by introducing mutations in a gene, or by eliminating the expression of a certain gene by deleting a part or all of the gene sequence from the genome of an organism.


Although less common than the evolution of antimicrobial drug resistance, vaccine resistance can and has evolved. How likely is it that COVID-19 vaccines currently in development will be undermined by viral evolution? We argue that this can be determined by repurposing samples that are already being collected as part of clinical trials. Such information would be useful for prioritizing investment among candidate vaccines and maximizing the potential long-term impact of COVID-19 vaccines.

Citation: Kennedy DA, Read AF (2020) Monitor for COVID-19 vaccine resistance evolution during clinical trials. PLoS Biol 18(11): e3001000. https://doi.org/10.1371/journal.pbio.3001000

Published: November 9, 2020

Copyright: © 2020 Kennedy, Read. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: The ideas presented here were developed during work funded by the Institute of General Medical Sciences, National Institutes of Health and United Kingdom Biotechnology and Biological Sciences Research Council as part of the NSF-NIH-USDA Ecology and Evolution of Infectious Diseases program (R01GM105244) to AFR and (R01GM140459) to DAK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

A safe and effective vaccine against COVID-19 would go a long way towards helping society return to its pre-pandemic normal. According to the World Health Organization, at least 198 COVID-19 vaccines are currently in the development pipeline, with 44 currently undergoing clinical evaluation [1]. That evaluation is, rightly so, focused on safety and efficacy. Here, we advocate for moderate additional effort during clinical trials to collect and publish data that can inform the risk of resistance evolution.

Much like antimicrobial drug resistance, vaccine resistance can and does evolve [2]. When it does evolve, vaccine resistance is achieved through mechanisms such as serotype replacement [3], antigenic change [4], or increases in disease severity [5]. However, for many vaccines, the evolution of resistance has never occurred [6]. For example, the measles vaccine has been widely used for decades without the virus ever evolving the ability to transmit through vaccinated hosts. Similarly, smallpox was completely eradicated, in large part due to vaccination that viral evolution failed to overcome. In contrast, Streptococcus pneumoniae quickly evolved resistance to the pneumococcal conjugate vaccine (PCV7), necessitating the development and deployment of a new vaccine, PCV13 [7]. Recently, the features that are critical to delaying the evolution of vaccine resistance have been described [6]. Here, we argue that by repurposing standard samples from COVID-19 clinical trials, the potential for vaccine resistance can be assessed even before vaccine licensure.

To our knowledge, all documented cases of vaccine resistance can be attributed to the absence of at least one of three key features that most vaccines possess: 1) the vaccine induces an immune response that protects hosts by targeting multiple virus epitopes simultaneously, thereby generating redundant and evolutionarily-robust protection, 2) the vaccine suppresses pathogen growth within hosts and stops transmission from vaccine-protected hosts, and 3) the vaccine-induced immune response protects against all circulating serotypes of the target pathogen. When feature 1 is present, resistance would likely require the appearance of multiple mutations, as opposed to just one, on the same genetic background. When feature 2 is present, little pathogen diversity would be generated during pathogen growth within vaccinated hosts, and the effects of selection on any resistance mutations that arose would be minimal. When feature 3 is present, new virus variants would need to be generated before resistance could be a problem, since vaccine resistance does not pre-exist. Combined together, these three features make the probability of resistance emergence vanishingly small [6].

It is important that the probability of resistance evolution be small because vaccine resistance can negatively impact public health. While antimicrobial drugs can be tailored to individual patients at the time of treatment, the choice of which vaccine to administer must be made well in advance of pathogen exposure. Should vaccine resistance emerge in the weeks, months, or years between vaccination and exposure, a vaccinated individual could be left unprotected. Should resistance become widespread and common, entire vaccination campaigns could retroactively be rendered ineffective. Moreover, since pre-existing antibodies frequently interfere with vaccine efficacy [8], we cannot assume that a new vaccine would be capable of restoring protection. Additionally, a large fraction of COVID-19 candidate vaccines target the spike protein of the virus or the receptor binding domain of the spike protein [9], and so the evolution of vaccine resistance against one vaccine could simultaneously undermine others, an outcome referred to as ‘collateral’ or ‘cross’ resistance in the case of antimicrobial drugs.

To avoid being caught off guard by the evolution of vaccine resistance, standard samples from clinical trials can be repurposed to assess the risk of resistance evolution even before a vaccine is licensed (Fig 1). First, blood samples are collected during almost all COVID-19 clinical trials to quantify individual responses to vaccination through antibody titer and serum neutralization tests. We propose that in addition to performing these tests, blood samples also be used to quantify the redundancy of immune protection generated by candidate vaccines [10,11]. Since redundant immune protection delays the evolution of vaccine resistance, much the same as combination drug therapy delays the evolution of antibiotic resistance, it is critical that vaccination induces immune responses against multiple non-overlapping viral epitopes. For SARS-CoV-2, as in other systems, resistance has already been shown to evolve quickly against monoclonal neutralizing antibodies relative to combinations of these antibodies [12]. Although yet to be shown for SARS-CoV-2, diverse T-cell responses can similarly delay resistance evolution [7]. Therefore, quantifying the redundancy of immune protection generated by vaccination is key information for determining the likelihood of resistance evolution.

1. The complexity of B-cell and T-cell responses can be measured using blood samples [10,11]. Different neutralizing antibodies are depicted above in different colors. More complex responses indicate more evolutionarily robust immunity. 2. The effect of vaccination on transmission potential can be assessed by collecting viral titer data using routine nasal swabs. Plaque assays from multiple vaccinated and control individuals are compiled into a histogram. Undetectable viral titers suggest little or no transmission potential, due to either complete immune protection or the absence of exposure. High viral titers suggest high transmission potential due to the absence of a protective immune response. Intermediate viral titers, marked above with an asterisk, suggest moderate transmission potential due to partial vaccine protection. Intermediate titers indicate an increased risk for resistance evolution since pathogen diversity can be generated within hosts and selection can act during transmission between hosts. 3. Pre-existing variation for vaccine resistance can be assessed by recovering genome sequences from nasopharyngeal swabs of symptomatic COVID-19 cases included in the study. In a placebo controlled, double blind study, any significant differences in the genome sequences of samples from vaccinated and control individuals would suggest at least partial vaccine resistance.

Second, many COVID-19 vaccine clinical trials collect weekly nasal swabs or fecal samples from vaccinated and control individuals to quantify vaccine protection against infection. We propose that these samples also be used to collect viral titer data as indicators of transmission potential. Strongly suppressing pathogen transmission through vaccinated hosts is key to preventing the spread of partial resistance should it arise, since it reduces the opportunities for selection to act [6]. While viral titer data are imperfect measures of transmission, they are a readily collectible proxy. Note that extra effort to collect higher quality transmission data may also be justifiable given the value of transmission data for optimizing vaccine distribution [13].

Third, many COVID-19 clinical trials collect nasopharyngeal swab samples from symptomatic vaccinated and control individuals to confirm SARS-CoV-2 as the causative agent of illness. We propose that viral genome sequences be generated from these swabs to look for evidence of vaccine-driven selection. For example, differences in allele frequencies between the viral genomes collected from vaccinated and control individuals would indicate selection [14], while simultaneously alleging a genetic basis for resistance [2, 3]. If such evidence were seen during a clinical study, as it can be [3], it would strongly indicate the potential for resistance to evolve.

A safe and effective COVID-19 vaccine is a priority, and it is urgently needed. Given this, we are not advocating to delay the release of a COVID-19 vaccine that is safe and efficacious even if there is a high likelihood that resistance will evolve against it. Rather, we are advocating that all vaccines be assessed as early as possible for the likelihood they will drive resistance evolution. As we explain above, this assessment can be conducted in a controlled manner during clinical trials, rather than first waiting for promising trial results to melt away after a vaccine is licensed.

For other diseases, vaccine failure due to pathogen evolution has occurred both during clinical trials [14] and after licensure [2]. We therefore suggest that the risk of resistance be used to prioritize investment among otherwise similarly promising vaccine candidates. If all first-generation vaccines are at appreciable risk of being undermined by virus evolution, it will be important to continue additional COVID-19 vaccine development following the discovery of a first, safe and efficacious vaccine. Predicting when and how resistance will be likely to evolve will give important insight into what needs to be monitored in phase IV studies after vaccine roll-out [3,7].

The world needs a COVID-19 vaccine urgently, just as the world previously needed drugs against tuberculosis and human immunodeficiency virus (HIV). It is tempting to leave evolutionary concerns until after a vaccine is introduced. But as we saw in the case of tuberculosis and HIV, the evolution of resistance can quickly undermine newly discovered interventions. By learning from solutions to previous evolutionary challenges, we can do better for COVID-19.


Could SARS-CoV-2 evolve resistance to COVID-19 vaccines?

UNIVERSITY PARK, Pa. -- Similar to bacteria evolving resistance to antibiotics, viruses can evolve resistance to vaccines, and the evolution of SARS-CoV-2 could undermine the effectiveness of vaccines that are currently under development, according to a paper published Nov. 9 in the open-access journal PLOS Biology by David Kennedy and Andrew Read from Penn State. The authors also offer recommendations to vaccine developers for minimizing the likelihood of this outcome.

Schematic illustrating three ways that standard samples from COVID-19 clinical trials can be repurposed to assess the risk that vaccine resistance will evolve. 1. The complexity of B-cell and T-cell responses can be measured using blood samples. Different neutralizing antibodies are depicted above in different colors. More complex responses indicate more evolutionarily robust immunity. 2. The effect of vaccination on transmission potential can be assessed by collecting viral titer data using routine nasal swabs. Plaque assays from multiple vaccinated and control individuals are compiled into a histogram. Undetectable viral titers suggest little or no transmission potential, due to either complete immune protection or the absence of exposure. High viral titers suggest high transmission potential due to the absence of a protective immune response. Intermediate viral titers, marked above with an asterisk, suggest moderate transmission potential due to partial vaccine protection. Intermediate titers indicate an increased risk for resistance evolution since pathogen diversity can be generated within hosts and selection can act during transmission between hosts. 3. Pre-existing variation for vaccine resistance can be assessed by recovering genome sequences from nasopharyngeal swabs of symptomatic COVID-19 cases included in the study. In a placebo controlled, double blind study, any significant differences in the genome sequences of samples from vaccinated and control individuals would suggest at least partial vaccine resistance.

"A COVID-19 vaccine is urgently needed to save lives and help society return to its pre-pandemic normal," said Kennedy, assistant professor of biology at Penn State. "As we have seen with other diseases, such as pneumonia, the evolution of resistance can quickly render vaccines ineffective. By learning from these previous challenges and by implementing this knowledge during vaccine design, we may be able to maximize the long-term impact of COVID-19 vaccines."

The researchers specifically suggest that the standard blood and nasal-swab samples taken during clinical trials to quantify individuals' responses to vaccination may also be used to assess the likelihood that the vaccines being tested will drive resistance evolution. For example, the team proposes that blood samples can be used to assess the redundancy of immune protection generated by candidate vaccines by measuring the types and amounts of antibodies and T-cells that are present.

"Much like how combination antibiotic therapy delays the evolution of antibiotic resistance, vaccines that are designed to induce a redundant immune response -- or one in which the immune system is encouraged to target multiple sites, called epitopes -- on the virus's surface, can delay the evolution of vaccine resistance," said Read, Evan Pugh Professor of Biology and Entomology and director of the Huck Institutes of the Life Sciences at Penn State. "That's because the virus would have to acquire several mutations, as opposed to just one, in order to survive the host immune system's attack."

The researchers also recommend that nasal swabs typically collected during clinical trials may be used to determine the viral titer, or amount of virus present, which can be considered a proxy for transmission potential. They noted that strongly suppressing virus transmission through vaccinated hosts is key to slowing the evolution of resistance, since it minimizes opportunities for mutations to arise and reduces opportunities for natural selection to act on those mutations that do arise.

In addition, the team suggests that the genetic data acquired through nasal swabs can be used to examine whether vaccine-driven selection has occurred. For example, differences in alleles, or forms of genes that arise from mutations, between the viral genomes collected from vaccinated versus unvaccinated individuals would indicate that selection has taken place.

"According to the World Health Organization, at least 198 COVID-19 vaccines are in the development pipeline, with 44 currently undergoing clinical evaluation," said Kennedy. "We suggest that the risk of resistance be used to prioritize investment among otherwise similarly promising vaccine candidates."


According to Dartmouth College, USA, research shows that past problems with vaccines can cause a phenomenon known as hysteresis, creating a negative perception that alters and hardens public resolve therefore causing vaccination resistance. The study explains why it is so hard to increase uptake even when overwhelming evidence indicates that vaccines are safe and beneficial.

The hysteresis cycle to vaccination resistance

A hysteresis loop causes the impact of a force to be observed even after the force itself has been eliminated. This is why unemployment rates can sometimes remain high in a recovering economy, or why physical objects resist returning to their original state after being acted on by an outside force. And, Dartmouth research suggests that this is why the public resists vaccination campaigns for ailments like the common flu.

Feng Fu, an assistant professor of mathematics at Dartmouth College explains: “Given all the benefits of vaccination, it’s been a struggle to understand why vaccination rates can remain stubbornly low.”

“History matters, and we now know that hysteresis is part of the answer.”

The research, published in the journal Proceedings of the Royal Society B, is the first study to demonstrate that hysteresis can impact public health.

“Once people question the safety or effectiveness of a vaccine, it can be very difficult to get them to move beyond those negative associations. Hysteresis is a powerful force that is difficult to break at a societal level.” adds Fu.

Vaccination resistance needs to stop

Low vaccine compliance is a public health issue that can cause the loss of ‘herd immunity’ and lead to the spread of infectious diseases. In parts of Europe and North America, childhood diseases like measles, mumps and pertussis have returned as a result of vaccination resistance .

“This study shows why it is so hard to reverse low or declining vaccine levels,” said Xingru Chen, a graduate student at Dartmouth and the first author of the research paper. “The sheer force of factual, logical arguments around public health issues is just not enough to overcome hysteresis and human behaviour.”

According to the research, the hysteresis loop can be caused by questions related to the risk and effectiveness of vaccines. Negative experiences or perceptions related to vaccination impact the trend of uptake over time, otherwise known to the researchers as a ‘vaccination trajectory’ that gets stuck in the hysteresis loop.

Hysteresis prevents an increase in vaccination levels even after the negative objections have been cleared, making society increasingly vulnerable to disease outbreaks.

“The coverage of measles vaccination has only gradually climbed up, but still remains insufficient, for more than a decade following the infamous MMR vaccination and autism controversy.” Chen concludes.

“Vaccination levels in a population can drop quickly, but, because of hysteresis, the recovery in that same population can take many years.”

By identifying the hysteresis effect in vaccination, the research team hopes that public health officials can design campaigns that increase voluntary vaccination rates, particularly by promoting vaccination as an altruistic behaviour that is desired by moral and social norms.

RELATED ARTICLESMORE FROM AUTHOR

A step closer to therapeutic interventions for Huntington’s disease

Scientific breakthrough could increase rhabdomyosarcoma survival rates

Tackling AMR and preventing the next global pandemic

New genetic discovery could improve treatment for neurological disorders

Over 2 million people in England may have had long COVID

Stem cell therapy could reduce AIDS virus and boost immunity

16 COMMENTS

Right…. because we naturally feel safer getting sick and healing, then injecting poison into our bodies… the human body has an immune system because we were built to get sick. Not fight to the brink of an autistic and sick world to prevent it.

Vaccines boost the immune system, you absolute weapon.

No they don’t. They put it overdrive and cause all kinds of Immune responses including autoimmune issues. Check the real inserts and tell me if anything in those vaccines are healthy. Unless you think heavy metal, DNA from humans, animals and insects are what you want in your body. Next to formaldehyde, polysorbate 80 and cancer cells, which are wonderful additions to your system.

LOL! They do not ‘boost” the immune system— they actually overextend and overexcite it And every system in the body. Now, vitamins can boost your immune system. You absolute weapon!

This is another reality-twisting propaganda piece by the pharmaceutical industry. Healtheuropa, you should be ashamed of publishing such blatant pseudoscience.

The reason people are questioning vaccines is educated people are doing their research. Why aren’t people getting a flu shot because when they look at the ingredients 30% of the multidose flu shots contain mercury as a preservative. Also they are not effective.
Flu vaccine : 630% more “aerosolized flu virus particles” emitted by people who received flu shots… flu vaccines actually SPREAD the flu
A l new scientific study published in the Proceedings of the National Academy of Sciences (PNAS) finds that people who receive flu shots emit 630% more flu virus particles into the air, compared to non-vaccinated individuals. In effect, this finding documents evidence that flu vaccines spread the flu, and that so-called “herd immunity” is a medical hoax because “the herd” is actually transformed into carriers and spreaders of influenza.

The finding is documented in a study entitled Infectious virus in exhaled breath of symptomatic seasonal influenza cases from a college community. The study authors are Jing Yan, Michael Grantham, Jovan Pantelic, P. Jacob Bueno de Mesquita, Barbara Albert, Fengjie Liu, Sheryl Ehrman, Donald K. Milton and EMIT Consortium.

Has the writer of this article done any research or just parroting the usual put out by vaccine manufacturers.
Mandatory vaccines to increase the profits of the vaccine manufacturers. Where are the studies that show vaccines are safe. The last study that the CDC did was 10 years ago and this is what the chief scientist said about those studies:

“My name is William Thompson. I am a Senior Scientist with the Centers for Disease Control and Prevention, where I have worked since 1998,” Thompson stated in August 2014 on the law firm’s website. “I regret that my coauthors and I omitted statistically significant information in our 2004 article published in the journal Pediatrics. The omitted data suggested that African American males who received the MMR vaccine before age 36 months were at increased risk for autism. Decisions were made regarding which findings to report after the data were collected, and I believe that the final study protocol was not followed.”

“Here’s what I shoulder. I shoulder that the CDC has put the research ten years behind. Because the CDC has not been transparent, we’ve missed ten years of research because the CDC is so paralyzed right now by anything related to autism. They’re not doing what they should be doing because they’re afraid to look for things that might be associated. So anyway, there’s still a lot of shame with that. So when I talk to a person like you who has to live with this day in and day out, I say well, so I have to deal with a few months of hell if all this becomes public, um, no big deal. I’m not having to deal with a child who is suffering day in and day out. So that’s the way I view all this. I’m completely ashamed of what I did. So that’s that.”

Here are some further quotes from William Thompson:
“I want to be absolutely clear that I believe vaccines have saved and continue to save countless lives. I would never suggest that any parent avoid vaccinating children of any race. Vaccines prevent serious diseases, and the risks associated with their administration are vastly outweighed by their individual and societal benefits.”

“The fact that we found a strong statistically significant finding among black males does not mean that there was a true association between the MMR vaccine and autism-like features in this subpopulation.”

….and yet they REFUSE to let him testify!

Vaccines do cause autism – this has recently been proven:
In 2007, Yates Hazlehurst’ father whose son developed severe autism after vaccination sued over his son’s injuries in the little known Federal Vaccine court. It was one of more than 5000 vaccine autism claims.
In 2007, Yates’ case and nearly all the other vaccine autism claims lost. The decision was based largely on the expert opinion of this man, Dr. Andrew Zimmerman, a world-renowned pediatric neurologist.
Dr. Zimmerman was the government’s top expert witness and had testified that vaccines didn’t cause autism. The debate was declared over.
But now Dr. Zimmerman has provided remarkable new information. He claims that during the vaccine hearings all those years ago, he privately told government lawyers that vaccines can, and did cause autism in some children and in the case of Hannah Poling, Dr Zimmerman testified that her autism was the result of vaccination triggering a rare mitochondrial disorder. Hannah Poling was awarded $20 million dollars but a gag order was put in place. That turnabout from the government’s own chief medical expert stood to change everything about the vaccine-autism debate. If the public were to find out.
Kennedy: This panicked the two DOJ attorneys and they immediately fired Zimmerman. That was on a Friday and over the weekend they called Zimmerman and said his services would no longer be needed. They wanted to silence him.
Kennedy: This was one of the most consequential frauds, arguably in human history.
Kennedy was instrumental in convincing Dr. Zimmerman to document his remarkable claim of the government covering up his true expert opinion on vaccines and autism.
Days after the Department of Justice lawyers fired Dr. Zimmerman as their expert witness, he alleges, they went on to misrepresent his opinion to continue to debunk autism claims. Records show that on June 18, 2007, a DOJ attorney Dr. Zimmerman spoke to told vaccine court, “We know [Dr. Zimmerman’s] views on the issue…There is no scientific basis for a connection” between vaccines and autism. Dr. Zimmerman now calls that “highly misleading.”
The former DOJ lawyer didn’t return our calls and emails. Kennedy has filed a fraud complaint with the Justice Department Inspector General, who told us they don’t “comment on investigations or potential investigations.”
Meantime, CDC—which promotes vaccines and monitors vaccine safety– never disclosed that the government’s own one-time medical expert concluded vaccines can cause autism – and to this day public health officials deny that’s the case.

Dr. Andrew Zimmerman Has now written and affidavit of truth stating the findings were FALSE and vaccinations do cause autism among many other things one of which is death.Vaccines kill and damage which is the real reason people do not want to vaccinate.

I developed lupus, rheumatoid arthritis and a whole host of autoimmune diseases/side effects of the Gardasil HPV vaccine. I was supposed to be protected from cervical cancer but instead had a hysterectomy for CERVICAL CANCER at 24!
The two children at had at age 19 and 23 both developed normally with normal genetic results. I haven’t heard my oldest son speak for 7 years as he is now completely non verbal, violent self injurious meltdowns after his MMR vaccine and in diapers forever requiring my care with SEVERE AUTISM. I delayed vaccines with my second child. It did not make a difference. He would clap and shout “good job” interrupting our church sermon only to be silenced and regress into severe autism after MMR. Vaccines are not one size fits all, they have not been proven safe!

Hysteresis Loop? Think of receiving vaccines as altruistic behavior? Are they listening to themselves? The BS meter went off the charts with this piece of drivel. Wow. Just wow! This article would be laughable if the consequences of injecting neurotoxins weren’t so deadly.

“The sheer force of factual, logical arguments around public health issues is just not enough to overcome hysteresis and human behaviour.”

Vaccine-savvy folks are still waiting for those “factual, logical arguments”. We have not heard them yet.

There seem to be two forces opposing the open examination of the links between Vaccination and Autism. The first is the belief by many people that the impact of vaccines is so overwhelmingly positive that any negatives (which are presumed to be minor) should be ignored/downplayed for the greater good. The second is determined groupthink by the medical establishment, governments and the pharmaceutical companies who have so much to lose if a proper investigation of the issue demonstrated that the cost:benefit ratio looked nothing like how they present it.
Whatever the truth is will be very hard to find out because there are many people and institutions who are determined to prevent proper investigations happening. Simultaneously, as further evidence accumulates showing how aluminium in vaccines causes inflammation in the brain, the options of parents to not have their children vaccinated are increasingly attacked.
The article is a good example of how the media promote the official line whilst ignoring the most important issues: the documented exponential increase in ASD and the conviction of many parents of children with neurological disorders that these were caused by vaccinations – for which scientific evidence continues to grow.


Contents

The immune system has two components: innate and adaptive immunity. The innate immunity is present in all metazoans, [2] while the adaptive immunity only occurs in vertebrates.

The innate system relies on the recognition of certain foreign molecules to stimulate two types of innate immune responses: inflammatory responses and phagocytosis. [3] The adaptive system, on the other hand, is composed of more advanced lymphatic cells that are programmed to distinguish between specific "non-self" substances in the presence of "self". The reaction to foreign substances is etymologically described as inflammation, meaning to set on fire. The non-reaction to self substances is described as immunity - meaning to exempt. These two components of the immune system create a dynamic biological environment where "health" can be seen as a physical state where the self is immunologically spared, and what is foreign is inflammatorily and immunologically eliminated. "Disease" can arise when what is foreign cannot be eliminated or what is self is not spared. [4]

Innate immunity, also known as native immunity, is a semi-specific and widely distributed form of immunity. It is defined as the first line of defense against pathogens, representing a critical systemic response to prevent infection and maintain homeostasis, contributing to the activation of an adaptive immune response. [5] It does not adapt to specific external stimulus or a prior infection, but relies on genetically encoded recognition of particular patterns. [6]

Adaptive or acquired immunity is the active component of the host immune response, mediated by antigen-specific lymphocytes. Unlike the innate immunity, the acquired immunity is highly specific to a particular pathogen, including the development of immunological memory. [7] Like the innate system, the acquired system includes both humoral immunity components and cell-mediated immunity components.

Adaptive immunity can be acquired either 'naturally' (by infection) or 'artificially' (through deliberate actions such as vaccination). Adaptive immunity can also be classified as 'active' or 'passive'. Active immunity is acquired through the exposure to a pathogen, which triggers the production of antibodies by the immune system. [8] Passive immunity is acquired through the transfer of antibodies or activated T-cells derived from an immune host either artificially or through the placenta it is short-lived, requiring booster doses for continued immunity.

The diagram below summarizes these divisions of immunity. Adaptive immunity recognizes more diverse patterns. Unlike innate immunity it is associated with memory of the pathogen. [6]

The concept of immunity has intrigued mankind for thousands of years. The prehistoric view of disease was that supernatural forces caused it, and that illness was a form of theurgic punishment for "bad deeds" or "evil thoughts" visited upon the soul by the gods or by one's enemies. [9] Between the time of Hippocrates and the 19th century, when the foundations of the scientific methods were laid, diseases were attributed to an alteration or imbalance in one of the four humors (blood, phlegm, yellow bile or black bile). [10] Also popular during this time before learning that communicable diseases came from germs/microbes was the miasma theory, which held that diseases such as cholera or the Black Plague were caused by a miasma, a noxious form of "bad air". [9] If someone were exposed to the miasma in a swamp, in evening air, or breathing air in a sickroom or hospital ward, they could get a disease.

The modern word "immunity" derives from the Latin immunis, meaning exemption from military service, tax payments or other public services. [11] The first written descriptions of the concept of immunity may have been made by the Athenian Thucydides who, in 430 BC, described that when the plague hit Athens: "the sick and the dying were tended by the pitying care of those who had recovered, because they knew the course of the disease and were themselves free from apprehensions. For no one was ever attacked a second time, or not with a fatal result". [11] The term "immunes", is also found in the epic poem "Pharsalia" written around 60 B.C. by the poet Marcus Annaeus Lucanus to describe a North African tribe's resistance to snake venom. [10]

The first clinical description of immunity which arose from a specific disease-causing organism is probably A Treatise on Smallpox and Measles ("Kitab fi al-jadari wa-al-hasbah'', translated 1848 [12] [13] ) written by the Islamic physician Al-Razi in the 9th century. In the treatise, Al Razi describes the clinical presentation of smallpox and measles and goes on to indicate that exposure to these specific agents confers lasting immunity (although he does not use this term). [10] The first scientist who developed a full theory of immunity was Ilya Mechnikov after he revealed phagocytosis in 1882. With Louis Pasteur's germ theory of disease, the fledgling science of immunology began to explain how bacteria caused disease, and how, following infection, the human body gained the ability to resist further infections. [11]

The birth of active immunotherapy may have begun with Mithridates VI of Pontus (120-63 B.C.). [14] To induce active immunity for snake venom, he recommended using a method similar to modern toxoid serum therapy, by drinking the blood of animals which fed on venomous snakes. [14] He is thought to have assumed that those animals acquired some detoxifying property, so that their blood would contain transformed components of the snake venom that could induce resistance to it instead of exerting a toxic effect. Mithridates reasoned that, by drinking the blood of these animals, he could acquire a similar resistance. [14] Fearing assassination by poison, he took daily sub-lethal doses of venom to build tolerance. He is also said to have sought to create a 'universal antidote' to protect him from all poisons. [10] [15] For nearly 2000 years, poisons were thought to be the proximate cause of disease, and a complicated mixture of ingredients, called Mithridate, was used to cure poisoning during the Renaissance. [16] [10] An updated version of this cure, Theriacum Andromachi, was used well into the 19th century.

In 1888 Emile Roux and Alexandre Yersin isolated diphtheria toxin, and following the 1890 discovery by Behring and Kitasato of antitoxin based immunity to diphtheria and tetanus, the antitoxin became the first major success of modern therapeutic Immunology. [10]

In Europe, the induction of active immunity emerged in an attempt to contain smallpox. Immunization, however, had existed in various forms for at least a thousand years. [11] The earliest use of immunization is unknown, however, around 1000 A.D. the Chinese began practicing a form of immunization by drying and inhaling powders derived from the crusts of smallpox lesions. [11] Around the fifteenth century in India, the Ottoman Empire, and east Africa, the practice of inoculation (poking the skin with powdered material derived from smallpox crusts) became quite common. [11] This practice was first introduced into the west in 1721 by Lady Mary Wortley Montagu. [11] In 1798, Edward Jenner introduced the far safer method of deliberate infection with cowpox virus, (smallpox vaccine), which caused a mild infection that also induced immunity to smallpox. By 1800 the procedure was referred to as vaccination. To avoid confusion, smallpox inoculation was increasingly referred to as variolation, and it became common practice to use this term without regard for chronology. The success and general acceptance of Jenner's procedure would later drive the general nature of vaccination developed by Pasteur and others towards the end of the 19th century. [10] In 1891, Pasteur widened the definition of vaccine in honour of Jenner and it then became essential to qualify the term, by referring to polio vaccine, measles vaccine etc.

Passive immunity is the transfer of immunity, in the form of ready-made antibodies, from one individual to another. Passive immunity can occur naturally, when maternal antibodies are transferred to the foetus through the placenta, and can also be induced artificially, when high levels of human (or horse) antibodies specific for a pathogen or toxin are transferred to non-immune individuals. Passive immunization is used when there is a high risk of infection and insufficient time for the body to develop its own immune response, or to reduce the symptoms of ongoing or immunosuppressive diseases. [17] Passive immunity provides immediate protection, but the body does not develop memory, therefore the patient is at risk of being infected by the same pathogen later. [18]

Naturally acquired Edit

Maternal passive immunity is a type of naturally acquired passive immunity, and refers to antibody-mediated immunity conveyed to a fetus by its mother during pregnancy. Maternal antibodies (MatAb) are passed through the placenta to the fetus by an FcRn receptor on placental cells. This occurs around the third month of gestation. IgG is the only antibody isotype that can pass through the placenta. Passive immunity is also provided through the transfer of IgA antibodies found in breast milk that are transferred to the gut of the infant, protecting against bacterial infections, until the newborn can synthesize its antibodies. Colostrum present in mothers milk is an example of passive immunity. [18]

Artificially acquired Edit

Artificially acquired passive immunity is a short-term immunization induced by the transfer of antibodies, which can be administered in several forms as human or animal blood plasma, as pooled human immunoglobulin for intravenous (IVIG) or intramuscular (IG) use, and in the form of monoclonal antibodies (MAb). Passive transfer is used prophylactically in the case of immunodeficiency diseases, such as hypogammaglobulinemia. [19] It is also used in the treatment of several types of acute infection, and to treat poisoning. [17] Immunity derived from passive immunization lasts for only a short period of time, and there is also a potential risk for hypersensitivity reactions, and serum sickness, especially from gamma globulin of non-human origin. [18]

The artificial induction of passive immunity has been used for over a century to treat infectious disease, and before the advent of antibiotics, was often the only specific treatment for certain infections. Immunoglobulin therapy continued to be a first line therapy in the treatment of severe respiratory diseases until the 1930s, even after sulfonamide lot antibiotics were introduced. [19]

Transfer of activated T-cells Edit

Passive or "adoptive transfer" of cell-mediated immunity, is conferred by the transfer of "sensitized" or activated T-cells from one individual into another. It is rarely used in humans because it requires histocompatible (matched) donors, which are often difficult to find. In unmatched donors this type of transfer carries severe risks of graft versus host disease. [17] It has, however, been used to treat certain diseases including some types of cancer and immunodeficiency. This type of transfer differs from a bone marrow transplant, in which (undifferentiated) hematopoietic stem cells are transferred.

When B cells and T cells are activated by a pathogen, memory B-cells and T- cells develop, and the primary immune response results. Throughout the lifetime of an animal, these memory cells will "remember" each specific pathogen encountered, and can mount a strong secondary response if the pathogen is detected again. The primary and secondary responses were first described in 1921 by English immunologist Alexander Glenny [20] although the mechanism involved was not discovered until later. This type of immunity is both active and adaptive because the body's immune system prepares itself for future challenges. Active immunity often involves both the cell-mediated and humoral aspects of immunity as well as input from the innate immune system.

Naturally acquired Edit

Naturally acquired active immunity occurs when a person is exposed to a live pathogen and develops a primary immune response, which leads to immunological memory. [17] This type of immunity is "natural" because deliberate exposure does not induce it. Many disorders of immune system function can affect the formation of active immunity such as immunodeficiency (both acquired and congenital forms) and immunosuppression.

Artificially acquired Edit

Artificially acquired active immunity can be induced by a vaccine, a substance that contains antigen. A vaccine stimulates a primary response against the antigen without causing symptoms of the disease. [17] Richard Dunning coined the term vaccination, a colleague of Edward Jenner, and adapted by Louis Pasteur for his pioneering work in vaccination. The method Pasteur used entailed treating the infectious agents for those diseases, so they lost the ability to cause serious disease. Pasteur adopted the name vaccine as a generic term in honor of Jenner's discovery, which Pasteur's work built upon.

In 1807, Bavaria became the first group to require that their military recruits be vaccinated against smallpox, as the spread of smallpox was linked to combat. [21] Subsequently, the practice of vaccination would increase with the spread of war.

There are four types of traditional vaccines: [22]

  • Inactivated vaccines are composed of micro-organisms that have been killed with chemicals and/or heat and are no longer infectious. Examples are vaccines against flu, cholera, plague, and hepatitis A. Most vaccines of this type are likely to require booster shots.
  • Live, attenuated vaccines are composed of micro-organisms that have been cultivated under conditions which disable their ability to induce disease. These responses are more durable, however, they may require booster shots. Examples include yellow fever, measles, rubella, and mumps. are inactivated toxic compounds from micro-organisms in cases where these (rather than the micro-organism itself) cause illness, used prior to an encounter with the toxin of the micro-organism. Examples of toxoid-based vaccines include tetanus and diphtheria. , recombinant, polysaccharide, and conjugate vaccines are composed of small fragments or pieces from a pathogenic (disease-causing) organism. [23] A characteristic example is the subunit vaccine against Hepatitis B virus.
  • DNA vaccines: DNA vaccines are composed of DNA encoding protein antigens from the pathogen. These vaccines are inexpensive, relatively easy to make and generate a strong, long-term immunity. [23]
  • Recombinant vector vaccines (platform-based vaccines): These vaccines are harmless live viruses that encode a one/or a few antigens from a pathogenic organism. They are used widely in veterinary medicine. [23][24][25]

Most vaccines are given by hypodermic or intramuscular injection as they are not absorbed reliably through the gut. Live attenuated polio and some typhoid and cholera vaccines are given orally in order to produce immunity based in the bowel.


Research explains public resistance to vaccination

Why is it so challenging to increase the number of people who get vaccinated? How does popular resistance to vaccination remain strong even as preventable diseases make a comeback?

A new study from Dartmouth College shows that past problems with vaccines can cause a phenomenon known as hysteresis, creating a negative history that stiffens public resolve against vaccination. The finding explains why it is so hard to increase uptake even when overwhelming evidence indicates that vaccines are safe and beneficial.

A hysteresis loop causes the impact of a force to be observed even after the force itself has been eliminated. It's why unemployment rates can sometimes remain high in a recovering economy. It's why physical objects resist returning to their original state after being acted on by an outside force. And, according to the Dartmouth research, it's why the public resists vaccination campaigns for ailments like the common flu.

"Given all the benefits of vaccination, it's been a struggle to understand why vaccination rates can remain stubbornly low," said Feng Fu, an assistant professor of mathematics at Dartmouth College. "History matters, and we now know that hysteresis is part of the answer."

The research, published in the journal Proceedings of the Royal Society B, is the first study to demonstrate that hysteresis can impact public health.

"Once people question the safety or effectiveness of a vaccine, it can be very difficult to get them to move beyond those negative associations. Hysteresis is a powerful force that is difficult to break at a societal level," said Fu, who led the research team.

Low vaccine compliance is a public health issue that can cause the loss of "herd immunity" and lead to the spread of infectious diseases. In parts of Europe and North America, childhood diseases like measles, mumps and pertussis have returned as a result of insufficient vaccination coverage.

Previous studies have combined behavior models with epidemiology to understand the challenge of voluntary vaccination, but have been unable to completely explain the persistence of low vaccine compliance. The Dartmouth research specifically studies how past problems associated with vaccinations can impact present and future vaccination decisions.

"This study shows why it is so hard to reverse low or declining vaccine levels," said Xingru Chen, a graduate student at Dartmouth and the first author of the research paper. "The sheer force of factual, logical arguments around public health issues is just not enough to overcome hysteresis and human behavior."

According to the research, the hysteresis loop can be caused by questions related to the risk and effectiveness of vaccines. Negative experiences or perceptions related to vaccination impact the trend of uptake over time -- known to the researchers as a "vaccination trajectory" that gets stuck in the hysteresis loop.

Hysteresis prevents an increase in vaccination levels even after the negative objections have been cleared, making society increasingly vulnerable to disease outbreaks.

"When it comes to vaccination levels, the past predicts the future. Unfortunately, this means that a lot of people are going to needlessly suffer unless we find a way to break the negative impact of the hysteresis loop," said Fu.

The study refers to the example of whole-cell pertussis vaccine in England and Wales in the period from 1978 through 1992. It took that 15-year span for uptake of the "whooping cough" vaccine to recover from 30 percent to 91 percent. According to the research team, such a recovery should only take about a year under ideal circumstances.

The research also notes the slow increase in measles vaccination in the face of resurgent outbreaks. In some countries, like France, measles has become an endemic disease despite the availability of an effective vaccine.

According to the study: "The coverage of measles vaccination has only gradually climbed up, but still remains insufficient, for more than a decade following the infamous MMR vaccination and autism controversy."

"Vaccination levels in a population can drop quickly, but, because of hysteresis, the recovery in that same population can take many years," said Chen.

For the common flu, the study suggests that a vaccine would have to have an effectiveness of above 50 percent in order to achieve high levels of vaccination, a difficult level to reach because of the speed with which the illness mutates.

By identifying the hysteresis effect in vaccination, the research team hopes that public health officials can design campaigns that increase voluntary vaccination rates, particularly by promoting vaccination as an altruistic behavior that is desired by moral and social norms.


The Need for Evolutionarily Rational Disease Interventions: Vaccination Can Select for Higher Virulence

There is little doubt evolution has played a major role in preventing the control of infectious disease through antibiotic and insecticide resistance, but recent theory suggests disease interventions such as vaccination may lead to evolution of more harmful parasites. A new study published in PLOS Biology by Andrew Read and colleagues shows empirically that vaccination against Marek’s disease has favored higher virulence without intervention, the birds die too quickly for any transmission to occur, but vaccinated hosts can both stay alive longer and shed the virus. This is an elegant empirical demonstration of how evolutionary theory can predict potentially dangerous responses of infectious disease to human interventions.

Citation: Boots M (2015) The Need for Evolutionarily Rational Disease Interventions: Vaccination Can Select for Higher Virulence. PLoS Biol 13(8): e1002236. https://doi.org/10.1371/journal.pbio.1002236

Published: August 25, 2015

Copyright: © 2015 Mike Boots. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Funding: The author received no specific funding for this work.

Competing interests: The author has declared that no competing interests exist.

There is little doubt that evolution continues to play a major role in preventing drug and vector-control programs from eliminating many infectious diseases. How much of the global infectious disease burden is attributable to recent evolution, and how much to social and other forces, remains unclear, but we are unquestionably severely impacted by the evolutionary potential of pathogens [1]. There is a large body of evolutionary theory that seeks to understand the processes that make some infectious diseases acute and lethal while others are chronic and mild [2–5]. More recently, this general theory has been applied to make predictions of the evolutionary outcomes of particular disease interventions within the broader aim of “virulence management” [6,7,9]. Of particular importance is that the theory predicts that there is the potential for certain disease interventions, including certain types of vaccination, to select for the evolution of greater virulence (cause higher mortality) and therefore present a greater threat to their hosts [7]. However, the theory generally makes deliberately simple assumptions, ignoring, for example, the molecular mechanisms that underpin host–parasite interactions. While this is one of the strengths of the approach—since it aims to make general predictions—it has been unclear how relevant this theory is to real infectious diseases. Read et al. have now provided a direct empirical test of one of the key theoretical predictions that “imperfect” vaccination can select for higher virulence [8]. The study is important because although there is increasing interest in evolutionary biology by the medical community [10,11], few empirical tests of evolutionary theory have been conducted that are of immediate relevance to important disease problems. Importantly, this empirical paper confirms the unintuitive and worrying predictions of a very simple theoretical model of the implications of a common disease intervention.

In some sense, theory on the evolution of virulence addresses the fundamental question of why infectious diseases kill their hosts. In a classic infectious disease, whether spread by contact, environmental infectious stages, or through vectors, the longer the host is infectious, the greater the chance that transmission will occur. If by killing the host the infectious period is shortened, then all things being equal, parasite genotypes that kill the host more slowly have a longer infectious period and will therefore be favored. Hence, virulence (defined as disease-induced mortality) will be selected against by evolution, and parasites should evolve to become benign they should evolve away from parasitism towards commensalism (infection without host damage). This is the “conventional wisdom” [3] that leads ultimately to the question: why are some parasites lethal? High virulence in a relatively rare host into which a disease occasionally spills over, such as Ebola in humans, may persist because selection is predominately occurring in the reservoir rather than the rare host. Furthermore, recently emerged, initially virulent disease may be in the process of evolving to lower virulence as they become more endemic in a new host. Also, in principle, disease-induced mortality could be a by-product of infection that is completely unrelated to both the genotype and life history characteristics of the parasite and is therefore not selected against. However, evolutionary theory assumes that virulence has been selected for because fundamentally things are not equal. Specifically, most theory assumes that disease-induced mortality (virulence) results from a “trade-off” (a gain in one trait comes at the expense of another) with another parasite characteristic, so that virulence is a correlated and unavoidable consequence of another factor that increases the chance of transmission. In this “trade-off hypothesis,” people have generally focused on virulence (mortality rate) being a by-product/cost of the transmission rate [2,5,12], as it is an appealing idea that high growth rates within the host may produce more transmission stages and therefore a higher rate of transmission, but also cause more damage and therefore higher virulence. Clearly within-host dynamics are much more complicated than this caricature, and we rarely understand all the mechanisms that underpin any trade-offs, but there is now good evidence for this overall relationship between transmission rate and mortality rate (virulence) in a number of systems [5,13–16]. Given this trade-off relationship, the theory predicts that there is an optimal transmission rate and level of virulence that maximizes the average number of infections that would occur in a completely susceptible population (the so called basic reproductive number, R0). With any disease intervention, however, there is a clear and present danger that the balance between transmission rate and virulence will be altered, leading to changes in “optimal” virulence. It is here that evolutionary theory can be useful in predicting the impact on infectious disease virulence of different interventions.

The theoretical paper that predicted the empirical results tested in the Read paper was inspired by the potential use of “imperfect” or “leaky” vaccines for malaria [7]. The key assumption of the model is that vaccination is “leaky” such that transmission can occur from infected, vaccinated individuals. If, on the other hand, the vaccination is “sterilizing,” preventing the infection (or at least the infectivity) of vaccinated individuals, then vaccinated individuals represent an evolutionary dead-end for parasites, as there is no opportunity for selection to occur. The model is simple in that it explicitly excludes escape mutants (which in some sense also make vaccines imperfect) and is typical of the approach used in evolutionary theory. The power of the approach is that by focusing on one process, the theory can make clear predictions. The key message of the detailed modeling is that leaky vaccination, which reduces the impact of the disease and thereby lowers pathogenicity, selects for a higher growth rate in the parasite, leading to a greater transmission rate and higher virulence [7]. Effectively, the cost of higher exploitation is reduced, which changes the shape of the virulence-transmission rate trade-off and allows for higher optimal growth and transmission rates. An important consequence is that a highly virulent parasite strain that kills its host so quickly that it cannot persist in an unvaccinated population can potentially circulate in a vaccinated population.

Read et al. present clear evidence that imperfect vaccines do indeed enable the persistence of much more virulent strains of Marek’s disease to circulate than would be possible in the absence of vaccination. Marek’s is a disease of poultry that is spread by inhalation, persists in the environment, and initially causes paralysis in older birds. Previous work from the group had shown clearly that there is a transmission-virulence trade-off in the disease [15,16]. Leaky vaccination [17] against Marek’s has been common since the 1970s, and over this period the disease has become much more virulent [12]. While during this time there have been a number of changes including the intensification of production [18] and shorter bird life spans [15] that could, in theory, have increased virulence, the Read paper directly examines whether leaky vaccines could be the cause. In the new paper, the vaccine is confirmed to be “leaky” [17]: vaccinated birds can become infected and, critically, they can shed the virus. In the core experiment, Read et al. vaccinated birds from naïve parents (so that there were no maternal antibodies) with five virus strains that vary in virulence from 60% mortality over two months to 100% mortality by 10 days. In terms of classic virulence measures, this approximates as a 10-fold variation in the disease-induced mortality rate. Vaccination does reduce shedding of the virus however, this positive effect of the intervention is overwhelmed in the more virulent viruses by the fact that unvaccinated birds die much more quickly. Without vaccination, the virulent strains generally kill the hosts before any transmission can take place: a strong example of the transmission virulence trade-off in action. The researchers went further and directly examined transmission using sentinel birds. These sentinel birds were put in enclosures with either vaccinated or unvaccinated birds, both of which had been challenged with the more virulent viruses. Early death in the unvaccinated birds meant that no sentinels were infected, and this contrasted starkly with the vaccinated birds enclosure, where the sentinel birds were infected. As a whole, this paper provides a direct test of the idea that vaccination allows the transmission of virus strains that are too virulent to transmit in non-vaccinated hosts.

A key criticism of the Gandon et al. theoretical paper is that there is no clear evidence of higher virulence due to human vaccination programs. However, the established successful human vaccination programs have mostly been “sterilizing” [19], although as we implement human vaccination programs with “leaky” vaccines, we will be carrying out real-world “experiments” that test the theory. The Read paper has shown, however, that this piece of evolutionary theory is pertinent to real-world infectious disease control. More generally, this study highlights the potential usefulness of evolutionary theory for disease control and suggests that it may therefore have an important role to play in the design of medical interventions. If so, it is important that we take a broad view of the evolution of virulence theory and the “trade-off hypothesis” beyond the simple relationship between transmission and mortality rates. Evolutionary theory is directly applicable whenever virulence is an optimum determined by the relative costs and benefits of a number of correlated parasite traits. This broader view is important since, for infectious agents that are obligate killers (i.e., they can only transmit at the death of their host), virulence is positively related to transmission. However, in these diseases there are other trade-offs, such as one between productivity and time to death, that lead to an evolutionarily optimal virulence that is determined by selection [5,20,21]. Indeed, the paper that is often cited as the origin of the trade-off hypothesis [4] described a trade-off between virulence (disease-induced mortality) and recovery (rather than transmission) such that faster growing, more damaging parasite strains are harder to clear, and the hosts take longer to recover [4,22]. Some of the criticism for the trade-off hypothesis focuses on whether there is a transmission–virulence relationship in a particular disease interaction but if we take this broad view, there is considerable evidence that virulence is shaped by selection [5,12,23]. Furthermore, although “accidental” high virulence in a rare host may not be selected against, selection is likely to be happening in the more common hosts, and even if virulence is caused primarily by host immunopathology, this has the potential to select the parasites to modulate growth or immunomodulation [24–27].

In terms of vaccination programs, it would clearly be useful if there were more experimental tests of the theory. However, there are likely to be few systems in which there has been the widespread historical implementation of leaky vaccination that are also amiable to experimentation. There are, however, a number of key issues that still need to be addressed theoretically. In particular, any vaccination program is likely to have incomplete vaccine coverage, and understanding the impact of different levels of heterogeneity in vaccine coverage within the population to the evolution of virulence is a difficult but important problem. Furthermore, there is likely to be genetic variation both in resistance of hosts and the efficacy of vaccination within most populations, and this heterogeneity may have important implications to the outcome of vaccination [28]. It is also the case that there can often be specificity between different parasite strains and host genotypes, and this may be of considerable importance in many systems [12], particularly outside of relatively genetically homogenous agricultural populations. That said, given that we now have this test in Marek’s disease, we are now able, at least, to say that the theory is relevant to real-world disease systems. It seems prudent, therefore, to take this risk seriously and consider the potential for selection in the use of new vaccines. The theory tells us that the key questions we need to ask of a vaccination program are: is the vaccine leaky? Does the vaccine act to reduce the impact of the disease within an individual? And is the virulence of the parasite selected for—whether it is due to the transmission virulence trade-off or some other, broader trade-off relationship? These questions should ideally be addressed before the implementation of any vaccination program, and careful monitoring would be usefully implemented in the light of this potential selection for higher virulence.

More broadly, other disease interventions beyond vaccination also have the potential to select upon disease and cause similar problems [6]. It is very hard for us to predict the evolutionary outcome after the emergence of a new disease into a population, but we can and should do much better in predicting the impact of our own disease interventions. If we take it seriously, evolutionary theory gives us the opportunity to move towards a more evolutionarily rational program of disease intervention. While the Read paper shows how the simple theory of the Gandon paper can predict real disease dynamics, there is considerable potential for the development of more disease-specific theory that includes more of the key detailed mechanistic knowledge of a particular host–parasite interaction. There is an opportunity for real advances in the predictive power of the models through tight collaborations between evolutionary modelers and molecular parasitologists and/or virologists. Calls for more serious acceptance of evolutionary biology by the medical community are increasing [10,11], and the Read paper shows that a combination of predictive theory and empirical tests of this theory in real-world disease systems have real potential to improve disease interventions in the light of evolutionary responses.


Could SARS-CoV-2 evolve resistance to COVID-19 vaccines?

Schematic illustrating three ways that standard samples from COVID-19 clinical trials can be repurposed to assess the risk that vaccine resistance will evolve. 1. The complexity of B-cell and T-cell responses can be measured using blood samples. Different neutralizing antibodies are depicted above in different colors. More complex responses indicate more evolutionarily robust immunity. 2. The effect of vaccination on transmission potential can be assessed by collecting viral titer data using routine nasal swabs. Plaque assays from multiple vaccinated and control individuals are compiled into a histogram. Undetectable viral titers suggest little or no transmission potential, due to either complete immune protection or the absence of exposure. High viral titers suggest high transmission potential due to the absence of a protective immune response. Intermediate viral titers, marked above with an asterisk, suggest moderate transmission potential due to partial vaccine protection. Intermediate titers indicate an increased risk for resistance evolution since pathogen diversity can be generated within hosts and selection can act during transmission between hosts. 3. Pre-existing variation for vaccine resistance can be assessed by recovering genome sequences from nasopharyngeal swabs of symptomatic COVID-19 cases included in the study. In a placebo controlled, double blind study, any significant differences in the genome sequences of samples from vaccinated and control individuals would suggest at least partial vaccine resistance. Credit: Kennedy et al, 2020 (PLOS Biology, CC BY 4.0)

Similar to bacteria evolving resistance to antibiotics, viruses can evolve resistance to vaccines, and the evolution of SARS-CoV-2 could undermine the effectiveness of vaccines that are currently under development, according to a paper published November 9 in the open-access journal PLOS Biology by David Kennedy and Andrew Read from Pennsylvania State University, U.S. The authors also offer recommendations to vaccine developers for minimizing the likelihood of this outcome.

"A COVID-19 vaccine is urgently needed to save lives and help society return to its pre-pandemic normal," said David Kennedy, assistant professor of biology. "As we have seen with other diseases, such as pneumonia, the evolution of resistance can quickly render vaccines ineffective. By learning from these previous challenges and by implementing this knowledge during vaccine design, we may be able to maximize the long-term impact of COVID-19 vaccines."

The researchers specifically suggest that the standard blood and nasal-swab samples taken during clinical trials to quantify individuals' responses to vaccination may also be used to assess the likelihood that the vaccines being tested will drive resistance evolution. For example, the team proposes that blood samples can be used to assess the redundancy of immune protection generated by candidate vaccines by measuring the types and amounts of antibodies and T-cells that are present.

"Much like how combination antibiotic therapy delays the evolution of antibiotic resistance, vaccines that are designed to induce a redundant immune response—or one in which the immune system is encouraged to target multiple sites, called epitopes—on the virus's surface, can delay the evolution of vaccine resistance," said Andrew Read, Evan Pugh Professor of Biology and Entomology and director of the Huck Institutes of the Life Sciences. "That's because the virus would have to acquire several mutations, as opposed to just one, in order to survive the host immune system's attack."

The researchers also recommend that nasal swabs typically collected during clinical trials may be used to determine the viral titer, or amount of virus present, which can be considered a proxy for transmission potential. They noted that strongly suppressing virus transmission through vaccinated hosts is key to slowing the evolution of resistance, since it minimizes opportunities for mutations to arise and reduces opportunities for natural selection to act on those mutations that do arise.

In addition, the team suggests that the genetic data acquired through nasal swabs can be used to examine whether vaccine-driven selection has occurred. For example, differences in alleles, or forms of genes that arise from mutations, between the viral genomes collected from vaccinated versus unvaccinated individuals would indicate that selection has taken place.

"According to the World Health Organization, at least 198 COVID-19 vaccines are in the development pipeline, with 44 currently undergoing clinical evaluation," said Kennedy. "We suggest that the risk of resistance be used to prioritize investment among otherwise similarly promising vaccine candidates."


Methods and materials

Ethics statement

All bird experiments were approved by the Avian Disease and Oncology Laboratory IACUC, US National Poultry Research Center, United States Department of Agriculture, approval number: Avian Disease and Oncology Laboratory (ADOL) 2016–07. Our animal care and use protocol adhered to the Animal Welfare Act (AWA), United States Department of Agriculture (USDA), and Animal Plant Health Inspection Service (APHIS). All experiments were carried out in custom-made negative pressure Horsfall-Bauer isolators [67]. A scoring system was developed and approved by the ADOL IACUC for monitoring progression of MD and for determining humane endpoints (SOP #9). Humane endpoint criteria include body posture, neurological signs, eye closure, response to stimuli, and ability to eat and drink. Chickens experiencing clinical signs of MD were immediately humanely euthanized upon reaching the prescribed clinical sign score. The euthanasia method was carbon dioxide gas inhalation, based on AVMA Guidelines for the Euthanasia of Animals 2020.

Transmission experiments

Experiments were carried out at USDA, ARS, USNPRC, ADOL, East Lansing, USA, during 2018. All experiments used 15I5 × 71 white leghorn chickens, a F1 hybrid cross of MD-susceptible 15I5 males and 71 females [43]. These maternal antibody-negative chickens were reared from a SPF breeding flock housed in isolators that have received no MD vaccination or exposure. The flock was negative for MDV antibodies and also for exogenous avian leukosis virus and reticuloendotheliosis virus, as established by routine surveillance testing.

The experiments involved 2 types of shedders, with shedder birds either vaccinated at hatch via intra-abdominal (IA) inoculation with 2,000 PFU of HVT (Meleagrid alphaherpesvirus 1) [33] or sham-vaccinated with PBS. Each shedder bird was then challenged with 500 PFU of virulent MDV (strain JM/102W) at 5 DPV (0 DPI). Each contact group of birds within each replicate consisted of 3 shedder birds of the same vaccination treatment (HVT or PBS) to be placed in contact with 15 unvaccinated, uninfected contacts (Fig 1). The 3 shedders were placed with the first group of 15 uninfected contacts at 13 DPI for 48 hours before being removed back to their isolator at 15 DPI. They were then placed with a second group of 15 contacts at 20 DPI until 22 DPI. Contact chicks were hatched weekly so that all contact birds were within 4 days of age when shedders were first introduced. There were 16 replicates consisting of paired lots of shedder birds (1 lot with 3 vaccinated shedders put into contact with 15 contacts at the 2 time points and the other with 3 sham-vaccinated shedders) and 4 further sham-vaccinated only replicates. These additional replicates were carried out because of early death of 2 sham-vaccinated shedders involved in the earlier replicates.

Shedders were then monitored until 8 weeks post-infection and contacts until 8 weeks post-contact and mortality (death or euthanasia) recorded. Necropsy was carried out at 8 weeks or upon death, whichever was the sooner, to determine the presence and severity of MD symptoms.

Blood (100 μl) and primary feather samples were taken from shedders at the start of each contact period (13 and 20 DPI) and from contacts at 14 DPC. Based on earlier experiments, 14 DPC was sufficient for build-up of virus in blood and feathers but early enough to avoid cross-contamination from other contact birds (S4 Text, S4 Fig). If HVT vaccine virus transmission occurred, 14 days would also be sufficient for HVT to replicate to close to its maximum viral load in the new host [36–38,68]. DNA samples isolated from feather pulp and PBLs were used for qPCR to determine virus load. Each measurement was taken from a unique sample.

DNA from each tissue type was isolated using the Puregene DNA isolation kit (Gentra System, Minneapolis, MN) followed by a multiplex PCR using methods as previously described for MDV [69] and HVT [70]. The TaqMan assay used FAM-TAM probes for virus gB and VIC-TAM probes for the cellular GAPDH. Results were reported as the ratio of virus gB copies per GAPDH copies, estimated using standard curves consisting of 10-fold serial dilutions of plasmids containing either virus gB or GAPDH. Amplifications were performed at Michigan State University, USA, using the ABI Quant Studio 7Flex BI 7500 (Carlsbad, California).

Statistical analyses

At total of 42 of 1,080 contacts were removed from the data set prior to analysis because of chick mortality (death up to 7 days old), with some further filtering for data quality and death by other causes. Final sample sizes were 211 (shedder FVL as response), 1,005 (infected contacts only), 789 (diseased contacts only), and 1,023 (all contacts regardless of infection or disease status). The transmission experiments were analysed using various linear and generalized linear mixed models in R version 3.6.0 [71], depending on the type of the response variable (Table 3). Regression analyses followed the logic of process analysis [72] to assess the role of pathogen load in mediating shedder vaccination effects on contacts—details below. Nonmetric multidimensional scaling for Fig 2B was carried out in PC-ORD version 7.0 [73] statistical software. All statistical tests were two-sided. No adjustments were made for multiple comparisons.

First, we tested the direct treatment effect (shedder vaccination status) on the outcome variables (contact disease variables, Table 3). The model formulae also included as fixed effects contact bird sex and shedder DPI, and a vaccination status by DPI interaction, which was removed if nonsignificant. Replicate and contact group nested within replicate were included as random effects in all models except for the survival analysis, for which contact group and replicate were included as clustering variables. Each contact individual was treated as a data point. For this and all subsequent analyses, testing contact FVL as response involved all contact individuals, infected or uninfected (Table 3). Contact binary disease status and mortality analyses involved infected (from qPCR) contacts only, and disease severity variables (tumours and nerve enlargement) involved diseased (from necropsy) contacts only.

Second, we carried out a process analysis, for which we tested all intermediate steps in the following proposed causal chain (see Fig 5): We hypothesized that the impacts of shedder vaccination status on the various contact infection and disease variables were primarily mediated by the vaccine effect on shedder FVL. More specifically, we hypothesized that shedder vaccination directly reduces shedder FVL and consequently also the exposure dose of contacts. The resulting lower exposure dose may reduce the probability of becoming infected and/or may lead to lower ingestion dose and consequently also to lower viral load in infected contacts. Lower contact viral load reduces the probability in infected contacts of developing visible disease symptoms or dying within the 8-week experimental period and also reduces disease severity among individuals positive for symptoms at necropsy. Eight weeks is also sufficient time for infected contacts to become infectious themselves and for disease development to occur in contacts infected by other contacts. Hence it was necessary to also consider the FVL of infected group mates alongside shedder and contact FVL in the process analysis.

Transmission of HVT was nonzero but nevertheless too low in a subsample of 6 contact bird groups to explain the vaccination effect (see Results section) and was therefore not explicitly included in our process analysis. We began the process analysis by testing whether shedder FVL explained a similar amount of contact bird disease variation as shedder vaccination status, by replacing shedder vaccination status with shedder FVL in the model formula described in the first step above. We then tested to what extent shedder FVL was affected by vaccination and then to what extent contact FVL and the sum FVL of each contact bird’s groupmates (hereafter denoted as groupmate FVL) were affected by vaccination and shedder FVL. Thus, for contact FVL and groupmate FVL as response variables, the model formulae were the same as described in the first step above, with the addition of sum of shedder FVL for each contact group as a fixed effect. Conversely, when shedder FVL was tested as a response variable, we used each individual shedder feather sample as a data point, and hence there were 2 data points per shedder individual (13 and 20 DPI). For this test, we used the same fixed effects model formula as described in the first step above, while replicate and shedder individual were included as random effects, the latter to account for repeated measures.

The values for contact FVL at 14 DPC were calculated as log10(contact FVL + 1 × 10 −5 ) for each individual. The contact groupmate FVL variable was the sum of FVL at 14 DPC of all 15 contacts in a group, minus the value for the focal individual. This variable was also analysed as log10(groupmate FVL + 1 × 10 −5 ). For shedder FVL as a predictor, we calculated log10(sum(shedder FVL + 1 × 10 −5 )) across the 3 shedders, from feather samples collected at the start of the contact period with each group of 15 contacts (13 and 20 DPI).

Third and finally, we tested whether shedder vaccination status exerted any effect on contact disease variables when controlling for mediating effects (shedder, contact, and contact groupmate FVL). If shedder vaccination status were to be rendered nonsignificant when tested alongside FVL variables, this would support the hypothesis that shedder vaccination impacts on contact disease were fully mediated by their effects on FVL. We first added shedder FVL alone to the basic model described in step 1, above, to test whether this variable was an effective bioindicator of shedder vaccination effects in secondary cases (infected contacts). We then further added contact and groupmate FVL to the model. Same-individual viral load is expected to be the strongest indicator of disease status, and so we expected shedder vaccination status and shedder and groupmate FVL to become nonsignificant in this model.

To examine whether the presence of even undetectably small quantities of vaccine virus in contact birds might affect the causal relationship between same-individual viral load and disease development, we carried out further multiple regression analyses with contact FVL nested within shedder vaccination treatment. For each response variable, we used a mixed-effects model with the same random effects as described above, and fixed effect predictors shedder vaccination status, shedder DPI, and contact bird sex alongside the nested contact FVL predictor.



Comments:

  1. Sagami

    Thank you, can I help you with something too?

  2. Kord

    There is nothing to say - keep silent, so as not to clog the topic.

  3. Malajinn

    I like this sentence :)

  4. Joachim

    Thank you)))))) in the quotation book!

  5. Liwanu

    what abstract thought



Write a message