How do you explain “herd immunity” to un-informed (or just stupid) people?

My experience teaches me that explaining things to uninformed people could be worth the effort. Not sure the same applies to stupid people. With that proviso out of the way, let’s get to brass tacks about herd immunity.

Some individuals within a population cannot be vaccinated,

  • Newborn and elderly.
  • Immunosuppressed people, from transplant-associated medications or chemotherapy for example.
  • Immunodeficient people, from genetic conditions for example.

How to protect them from vaccine-preventable infections present in their community? That’s where herd immunity comes in.

At its simplest, herd immunity is a function of an infection’s basic reproduction number (infectiousness).

  • It represents the infection’s potential for spread.
  • It is the theoretical average number of susceptible individuals who could be infected from a single infected person.

A picture is worth a thousand words or so they say so here goes with an extremely crude oversimplification.

Herd immunity: What it does

  • Provides a protective barrier against infection across an entire population.
  • Each individual immune either from getting infected naturally or from vaccination forms a part of this barrier.
  • Limits or entirely prevents transmission of a given infection.
  • More immune individuals within a population, more likely infection transmission stops before reaching all potentially susceptible individuals in it.
  • Indirectly protects from infection those vulnerable susceptible individuals who cannot be vaccinated either because the vaccine hasn’t been approved for their age group or because of problems with their immune system.
  • Also indirectly protects those who refuse to get themselves or their children vaccinated, the so-called free riders.

Herd immunity: What it is

Also known as community immunity,

  • It is an estimate of how many need to be immune in order to protect an entire population from a specific infection.
  • An infected person is more likely to spread infection earlier rather than later in an outbreak since longer it lasts, lower the number of susceptible individuals as more and more have already caught the infection.
  • The herd immunity threshold differs for each infectious disease agent and depends on,
    • The organism’s infectiousness: how many people can get infected from contact with one infected person.
    • Duration of infectivity: length of time an infected person can spread the infection.
    • Number of susceptible people in a population who come in contact with an infected person when they are infectious.
    • How well a given vaccine prevents infection transmission.
    • How long immunity from vaccination or natural infection lasts.
    • Whether or not infection spreads from human-to-human alone or from other animals as well.
  • This threshold is obviously highly dynamic.
    • Since the immune and the susceptible aren’t spread out evenly across a population, herd immunity threshold can vary widely between pockets within it.
    • Pockets that allow non-medical exemptions for vaccination will have much higher concentrations of those susceptible even within a larger population with fairly high vaccination levels. This explains local outbreaks such as measles breaking out within a specific geographic area. One reason measles breaks out so readily in such pockets is because it has one of the highest basic reproduction numbers of 12 to 18 and thus correspondingly has a herd immunity threshold of 92 to 94%, meaning that that 92 to 94% within a population need to be measles-vaccinated in order for the unvaccinated to remain protected.
    • Unless an infection has been eradicated worldwide, neither risk of catching it nor risk of harming others who cannot be vaccinated are zero.


Does every single cell in my body have the same DNA?


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In the age of the microbiome the phrase ‘we contain multitudes’ has become something of a tiresome trope. Its triteness notwithstanding, it remains true in more ways than one because not only are microbes among such multitudes but genetically different human cells are also part of the mix. Trust pesky science to ensure that ‘who am I’ becomes an ever trickier metaphysical question to tackle!

Two natural phenomena, chimerism and mosaicism, and an artificial one, transplantation, which also introduces chimerism, can and often do stand in the way of all cells in our body having the same DNA.


In Greek mythology chimeras were monstrous hybrids of different animals. In humans, chimeras are individuals with more than one genetically distinct cell population. Chimeras result from two ways,

  • Dizygotic twins who exchange cells with each other during gestation. In such cases often twins are born or more rarely, only one baby is born but is found to have two genetically distinct cell populations suggesting dizygotic twins started during development but at some time thereafter one fused with the other. How often does such fusion of dizygotic twins occur? No one knows because they are usually only discovered accidentally when the chimera donates blood or other samples.
  • Feto-maternal microchimerism where mother and baby exchange cells with each other during gestation and some of these genetically distinct cells can last in each other’s bodies long after, sometimes years or even decades. The term microchimerism is used because usually <1% of dividing cells are chimeric (below from 1).

Such feto-maternal microchimerism usually passes without notice, only punching through in the context of unusual clinical findings during either disease or its resolution. I wrote about one such example in a post several years back (below from 2),

“Chimerism revealed*. For an unnamed woman, subject of a 2002 study**, it started with Hepatitis C. No history of transfusion. Five known pregnancies with four partners. One son delivered at full term. Unexpectedly high number of male cells in her liver biopsies. As Hepatitis C ravaged her liver, it appears that long-lived fetal microchimeric cells, maybe stem cells, remnants of one of her pregnancies, made their way from somewhere inside her body to her damaged liver and differentiated into hepatocytes, to help, to try to heal.

* While the labs of Diana W. Bianchi, J. Lee Nelson and others are modern-day pioneers in revealing to us the chimeras we are, our scientific literature suggests we had some knowledge of this since at least the 19th century.

**Significant fetal cell microchimerism in a nontransfused woman with hepatitis C: Evidence of long-term survival and expansion”


Typically in transplantation a recipient gets genetically non-identical donor tissue or organ (allografts). While powerful immunosuppressant drugs help prevent the rejection of such genetically different donor tissue, a large body of work now shows that chimerism, engraftment of donor cells within the recipient’s body, greatly helps in helping the recipient immunologically tolerate the allograft tissue.


Genetic mosaicism is when there’s a mutation very early during cell division within a single fertilized egg. The progeny of such a mutated cell also carry that mutation.

Mosaicism is usually only discovered during the course of serious disease as a New York Times article reported in May 2018 (below from 3),

“James Priest couldn’t make sense of it. He was examining the DNA of a desperately ill baby, searching for a genetic mutation that threatened to stop her heart. But the results looked as if they had come from two different infants.

“I was just flabbergasted,” said Dr. Priest, a pediatric cardiologist at Stanford University.

The baby, it turned out, carried a mixture of genetically distinct cells, a condition known as mosaicism. Some of her cells carried the deadly mutation, but others did not. They could have belonged to a healthy child.

We’re accustomed to thinking of our cells sharing an identical set of genes, faithfully copied ever since we were mere fertilized eggs. When we talk about our genome — all the DNA in our cells — we speak in the singular.

But over the course of decades, it has become clear that the genome doesn’t just vary from person to person. It also varies from cell to cell. The condition is not uncommon: We are all mosaics.”


1. Kinder, Jeremy M., et al. “Immunological implications of pregnancy-induced microchimerism.” Nature Reviews Immunology 17.8 (2017): 483.

2. Our Identity: Part Three
The Biology of Us versus our Politics of Identity. The Profound versus the Profane. by Tirumalai Kamala on TK Talk

3. Every Cell in Your Body Has the Same DNA. Except It Doesn’t.

What are the benefits that vaccinations, especially childhood vaccinations have brought to humanity?

The moral of the story of vaccines seems to be, at least to me, that an embarrassment of riches can breed complacence, even contempt.

A largely overlooked segment in the overheated debate on vaccines are pets and other animals who live among us and can’t advocate for themselves in our midst.

While a vaccine helped eradicate rinderpest, vaccines for anthrax, distemper, feline leukemia, infectious hepatitis, parvo virus, rabies and tetanus have helped companion animals such as cats and dogs as well as livestock such as cattle and sheep live longer and healthier lives. Aren’t pets after all considered a part of human families, even akin to children?

Moving on from pets to humans, unlike scientific experiments conducted in labs, where all kinds of factors can be tightly managed to allow controlled testing of one or few variables at a time, real life is messy and many variables change simultaneously. Messiness of real life means that as causative agents of various infectious diseases were discovered and isolated starting in the late 19th century, vaccine development and deployment went hand in hand with dramatic improvements in hygiene, nutrition and sanitation as well as discovery and widespread use of antibiotics (below from 1).

However, while hygiene and sanitation helped reduce infectious disease spread and thus helped bring deaths (mortality) down, they didn’t eliminate such infections altogether. Costs to individuals in the form of illnesses (morbidity) and irreversible consequences (think paralysis from polio) of such illnesses stayed high as did the collateral cost to societies.

Even in the US, which had attained fairly high levels of hygiene and sanitation by the mid-20th century, specific infectious disease cases such as mumps, polio, rubella and measles only declined to near zero after vaccines against them were licensed and began to be deployed starting in the 1960s (below from 2, 3). Children are the major beneficiary since historically they bore the disproportionate brunt of infectious disease costs in the form of both morbidity and mortality.

Considering vaccine are deployed in places with vastly varying levels of hygiene and sanitation, not to mention lack of guarantees as to reliable access to adequate nutrition, similar worldwide trends hint at the power of vaccines in thwarting specific infections, (below from 4).

Thus, while on the one hand we’ve set about dramatically changing our lifestyles over the past century and in the process engendered chronic diseases such as cardiovascular diseases and diabetes that take their toll mid-life to old age, on the other hand, we’ve managed to rout some infectious diseases that used to cost much in terms of illness, disability and death, especially in children younger than five.

Vaccine explains the eradication of a deadly viral disease such as smallpox, which was a major source of all-cause mortality until even well into the 20th century (below from 5). I should know. I’m here only because my mother luckily survived smallpox.

Quite a deadly disease, several factors about both smallpox and its attenuated vaccine were crucial in helping eradicate this disease by 1980 (6),

  • On the one hand, smallpox spreads human-to-human with no animal reservoir and causes characteristic skin lesions that are very easily recognizable, which helped track cases.
  • On the other hand, the attenuated smallpox vaccine didn’t need the cold chain and could be injected very simply subcutaneously, by a bifurcated needle holding just the optimal vaccine dose between its two prongs jabbed into the skin. This made it technically easy to administer it out in the field in all sorts of conditions.
  • To eradicate smallpox during the last stages, people were offered rewards to report suspected cases and individuals around such cases were also vaccinated in a strategy that came to be known as ring vaccination.

Thus it came about that smallpox was declared eradicated in 1980.




3. Impact of vaccines in 20th and 21st centuries

4. World Health Organization (WHO). “Vaccine Safety Basics learning manual.” Geneva: WHO (2013).…

5. Fenner, Frank, et al. “Smallpox and its eradication. 1988.” Geneva, Switzerland: World Health Organization.…

6. Halloran, M. Elizabeth, et al. Design and analysis of vaccine studies. New York:: Springer, 2010.…

Are vaccine studies meaningless because they look at antibody responses and not any real result such as mortality?

If vaccines only helped stave off mortality, it would be fair to question the value of vaccine studies that only examine antibody responses. However, not only do vaccines help mediate other outcomes, who they are intended for, how they might work and how to assess that they work, the complexities and limitations imposed by these parameters led over time to antibody measurements getting established as among the most common of predictors for vaccine effectiveness, aka Correlates of immunity/correlates of protection – Wikipedia.

Vaccine development, like that of medicines in general, is an empirical process of trial and error, schooled by the adage to not let the perfect be the enemy of the good. Optimal readouts for some vaccines, antibody responses are less than optimal for others but will have to do until other more optimal readouts get validated in each and every case.

This answer explains

  • How vaccines do more than prevent mortality.
  • How being intended for healthy people precludes ethical ways to test whether vaccines protect humans against mortality.
  • Assessing vaccine protectiveness thus necessitates assessing correlates (predictors) of protection that serve as surrogates for true effectiveness, which itself is different for different vaccines.
  • That antibodies are optimal correlates of protection for several infections but fall short for others. Plugging the gap in the latter cases is the current focus of much vaccine research.

A vaccine can do more than prevent mortality.

  • Does it prevent infection altogether,
  • Does it prevent symptomatic infection,
  • Does it prevent severe disease, or,
  • Does it prevent an infection from spreading from the infected person?

Each of these essential public health goals are hardly interchangeable.

Outcomes from infections aren’t interchangeable either and neither is mortality the only inevitable outcome of an infection.

  • Some infections, like ebola, indeed carry the price tag of a high mortality rate after an acute infection.
  • Others, like hepatitis B and C, cause decades-long chronic infections that can even be asymptomatic for long periods of time.
  • Still others, like polio, can leave behind lifelong disability.
  • Infections such as the TORCHES (Toxoplasma, Other infections, Rubella, Cytomegalovirus, Herpes Simplex-2) or Vertically transmitted infection – Wikipedia may not necessarily kill an infected mother or even make her noticeably ill but can instead pass through to the fetus and either cause spontaneous abortion or severe developmental disorders.

Unlike medicines, vaccines are intended for healthy people, typically to protect them against infectious diseases and neither the vaccinee nor anyone else can predict whether that infection is around the corner from them, some months down the road or even years or decades into the future.

How to assess vaccine effectiveness? Vaccinate or not then infect both groups and then at different time-points kill a few from the vaccinated and unvaccinated groups, harvest various organs and tissues, culture them to quantify the infectious agent to assess how well the vaccine worked at preventing or controlling the infection. Standard approaches in animal models, such tests are obviously absolutely impossible in humans.

How then can we assess how well a vaccine works in humans? Vaccinate or not and then monitor the two groups over their lifetimes to see if the vaccine reduces mortality rate. Is there any country wealthy enough to validate each and every vaccine using such a prohibitively expensive approach? Rhetorical question. Not to mention, the infection in question would continue to ravage populations across the world. Such approaches do not a sensible public health policy make.

Since waiting over entire lifetimes to assess mortality rates is expensive beyond the pale and industrial age populations were indeed being felled in large numbers from rolling epidemics of several infectious diseases, vaccinologists had to come up with alternatives that served as adequate predictors for protection. Around that time, and long before anything much was known about the immune system, circulating antibodies revealed themselves as convenient predictors of vaccine effectiveness.

Where antibodies are optimal correlates of protection

  • Much of the visible spectacular successes of vaccines in the modern era is after all the success of the so-called antisera against rabies virus, and against toxin-producing bacteria such as diphtheria or tetanus. We now know antibodies are the critical and relevant protective components in such antisera and that they protect against these previously deadly infections that used to cause a great deal of mortality.
    • Even today, a person bit by a potentially rabid animal is largely assured of escaping an excruciatingly painful, terrible fate and certain death if they immediately get treated with post-exposure prophylaxis, a major component of which remains anti-rabies immunoglobulins (antibodies).
  • Vaccine-induced antibodies are now also known to be the crucial protective agents that help prevent severe disease in the case of infections caused by encapsulated bacteria such as bacterial flu caused by Haemophilus influenzae, meningitis caused by Neisseria meningitidis, and pneumonia and meningitis caused by Streptococcus pneumoniae. In such cases, vaccine-induced antibodies prevent the infection from seeding deeper into more vulnerable sites such as the brain and lungs from the initial sites of infection.

Where antibodies aren’t optimal correlates of protection

  • Vaccine-induced antibodies are far from optimal correlates of protection in many other infections, for example, in bacterial infections such as pertussis, tuberculosis, and in viral infections such as cytomegalovirus, dengue, ebola.
  • Antibody titer alone doesn’t fully represent the strength of protection a vaccine induces, its isotype and location can be equally important.
  • Memory CD4+, and less so, CD8+ T cells are just as critical predictors of vaccine effectiveness. However, standardized methods to quantify their numbers and functions relevant to vaccine protectiveness remain a critical gap in the vaccine field, largely because they haven’t yet been standardized in the immunology field itself.

Does specific antibiotic-resistant bacteria arise through overuse within an individual human, or does it require overuse across the larger population?

Given the sheer astronomical number of bacteria on earth, antibiotic resistance can arise at any time. However, as with any genetic variation, for antibiotic resistance to get fixed in a given bacterial population takes a two-step tango,

  • Gaining a new function such as a novel antibiotic resistance gene isn’t cost-free but instead carries a fitness cost because novel expression of antibiotic resistance emerges within a metabolic system that’s already worked its way through growing pains and learned to tick along nicely and now has to accommodate this new function. Being novel, this function may not be properly calibrated yet and thus may interfere with some essential bacterial function.
  • Next, fixing and maintaining antibiotic resistance takes strong selection pressure.

In practical terms, novel antibiotic resistance genes would more likely be selected against than for, except in those cases that happen to have low fitness cost. Absent selection pressure, antibiotic resistance would require genetic drift to get fixed in a given bacterial population.

Unfortunately, we are inadvertently imposing strong selection pressure, having created a world where both unnecessary individual as well as general use is rampant. Not only have the past few decades witnessed an epidemic of unnecessary antibiotic prescription, extensive antibiotic use in industrial livestock production has simultaneously emerged as a pervasive practice.

Does BiTE (bispecific T cell engager) have a similar limitation with CAR-T cells in solid tumors?

We need to consider CAR-T and BiTE structures and pharmacokinetics to appreciate their relative advantages and disadvantages.

The CAR-T approach tries to force an anti-tumor cell T cell response by genetically engineering T cells, usually derived from cancer patients themselves, to express a tumor targeting signaling molecule, the CAR part of CAR-T, on their cell surface.

  • CAR is a synthesized hybrid consisting of an extracellular single-chain variable fragment derived from an antibody that targets an antigen specifically expressed by the tumor.
  • The intracellular part of this hybrid signaling molecule consists of the ∂ portion of the CD3 molecule, which is an integral component of the T cell receptor’s signaling complex.
  • The idea is that the extracellular scFv portion of this hybrid molecule would bind a tumor cell while such binding would trigger signaling into the T cell through the intracellular CD3∂ portion and thereby activate the CAR-T cell, which would then kill the tumor cell.

Thus far, CAR-T cells have been found severely limited in their capacity to target solid tumors.

  • Tumor penetration: solid tumors tend to have a dense extracellular matrix that poses a formidable physical and metabolic barrier to immune cells in the form of a low pH, low oxygen, low nutrient environment rich in a variety of immunosuppressive cells and secretory factors (cytokines, chemokines).
  • Appropriate choice of target antigen: Many tumor-specific antigens turn out to be TAA, Tumor-Associated Antigens and not TSA, Tumor-Specific Antigens.
    • A CAR-T that targeted a TSA would be very specific, and bind and kill only tumor cells that expressed that TSA.
    • Targets of a CAR-T that targeted a TAA would be much broader and include normal, healthy tissue cells as well, which would become collateral damage.
    • Depending on how widespread is the expression of a TAA, the results could even be life-threatening. While TAAs are a dime a dozen, finding and validating a TSA is turning out to be akin to finding the proverbial extremely tiny needle in a ginormous haystack.

This may be why CAR-Ts have proven most effective thus far against blood cancers such as leukemias – for example, anti-CD19 CAR-Ts that target CD19-expressing B cell tumors – while they haven’t yet had success against solid tumors.

BiTEs are an entirely different – non-cellular – biotech approach to try to direct T cell responses against tumor cells. Bispecific T cell engagers are bispecific antibodies or diabodies, where one scFv binds the CD3 molecule on the T cell surface while its other scFv binds a cell-surface antigen expressed by the tumor cell.

Being quite small, ~50 to 55kDa, is an advantage for BiTEs in that they could easily penetrate the tumor. However, lack of TSAs similarly hampers BiTEs as it does CAR-Ts, which makes the BiTE trajectory appear quite similar to that of CAR-Ts.

  • Thus far only Blinatumomab – Wikipedia, which targets B cells in acute lymphoblastic leukemia, has FDA approval.
  • Another BiTE that has progressed in the development pipeline is Solitomab – Wikipedia, which targets the Epithelial cell adhesion molecule – Wikipedia, expressed on some GI tract, lung and other solid tumors.
    • A recently published phase I study (Kebenko, Maxim, et al. “A multicenter phase 1 study of solitomab (MT110, AMG 110), a bispecific EpCAM/CD3 T-cell engager (BiTE®) antibody construct, in patients with refractory solid tumors.” OncoImmunology (2018): e1450710.…) on 65 patients with EpCAM-positive tumors showed fairly high levels of tissue toxicity including severe diarrhea and increases in liver enzymes suggesting possibility of liver damage even at lower doses, symptoms which precluded being able to treat these patients with the much higher doses deemed therapeutic by earlier preclinical studies. Disappointing results such as these may signal the end of Solitomab.
  • Adverse outcomes apart, diabodies such as BiTEs have an additional limitation, namely quite a short half-life in vivo. They bind their targets alright but are quickly degraded and cleared within a handful of hours. Even in this phase I study, patients needed to be continuously infused intravenously over at least 4 weeks since Solitomab has a half-life of only 4.5 hours.

Though a considerable amount of basic research investment has gone into developing BiTEs over the past 10 to 15 years, their pharmacokinetic limitations suggest they may be more useful as imaging reagents rather than as mediators of cancer killing by T cells.

Given that intestinal flora seem to have an influence on personality, why aren’t probiotics being sold which are made from the gut bacteria of particularly well-adjusted people?


The question assumes

  • That intestinal microbiota can influence emotional states, and,
  • That probiotics derived from intestinal microbiota of particular ‘well-adjusted’* people should be able to make others who take them become similarly ‘well-adjusted’ as well.

While probiotics have some health benefits, we are currently far from understanding how they work nor are we able to harness them reliably.

While probiotics have become a multibillion dollar industry in the blink of an eye, many of the claims made about them are unsubstantiated and even flat out exaggerations (1). Clinical trials using probiotics in a variety of health conditions show promise here and there but nothing on the scale to match the ginned up, hyper-marketed claims made about them.

Proving the health benefit of any gut microbe or probiotic is an exceedingly steep challenge and certainly not easy since gut microbiota of even monozygotic twins, the closest we get in terms of genetically identical humans, diverge the longer they live apart (2, 3),

There’s also the all-important issue of definition. The WHO defines probiotics as (4)

live microorganisms which when administered in adequate amounts confer a health benefit on the host.

Contrary to slap happy marketers who in the absence of airtight regulations can casually sell dubious products as probiotics, actual probiotics are specific strains such as Lactobacillus rhamnosus GG, Lactobacillus casei Shirota, Bifidobacterium longum R0175, Lactobacillus helveticus R0052 and others. Each of these strains has been the subject of intense research for years, some even for decades.

The WHO further holds that probiotic benefit needs to be rigorously scientifically demonstrated for each specific strain for each specific usage (5). Indeed, probiotic benefit from even these well-defined and well-studied strains isn’t always guaranteed.

For example, just recently, two randomized double-blind, placebo-controlled trials found that Lactobacillus rhamnosus GG with or without Lactobacillus helveticus R0052 was unable to substantially reduce adverse outcome from acute infectious gastroenteritis in infants and children in the US and Canada (6, 7).

When even such large (n=1857) clinical trials as rigorously designed as possible are unable to substantiate that such well-studied probiotic strains can alleviate GI tract distress, the lowest of low hanging fruit in the probiotic benefit scale, proving that novel microorganisms isolated from GI tracts of ‘well-adjusted’ people are able to mediate beneficial changes in the dispositions of random others is beyond a tall order at this point in time.

Understanding probiotic health benefits first requires understanding how they work in each instance. Next, predictable outcomes in the exceedingly messy real world requires understanding how major factors such as diets, medications, diseases and genetic polymorphisms influence such benefits.

Intestinal microbiota are now considered to influence different aspects of human physiology, including neurophysiology. However, if gut microbiota can indeed reliably alter mental states, which remains to be proved, it’s yet entirely unclear how they might do so, which specific microbes and/or microbial products are involved in such a process, whether and how confounding variables such as specific diets, medications, underlying health conditions and/or unidentified genetic polymorphisms help or impede in maintaining such microbes and in influencing their effects (functions). Deriving probiotics from such intestinal microbiota is even further removed from practical realization at present.

*for any probiotic effect to be able to work in a predictive manner, the term ‘well-adjusted’ requires an objective definition.


1. The Problem With Probiotics

2. Xie, Hailiang, et al. “Shotgun metagenomics of 250 adult twins reveals genetic and environmental impacts on the gut microbiome.” Cell systems 3.6 (2016): 572-584. ScienceDirect

3. Rothschild, Daphna, et al. “Environment dominates over host genetics in shaping human gut microbiota.” Nature 555.7695 (2018): 210.…

4. Hotel, Amerian Córdoba Park. “Health and Nutritional Properties of Probiotics in Food including Powder Milk with Live Lactic Acid Bacteria.” PREVENTION 5 (2001): 1.…


6. Freedman, Stephen B., et al. “Multicenter trial of a combination probiotic for children with gastroenteritis.” New England Journal of Medicine 379.21 (2018): 2015-2026.

7. Schnadower, David, et al. “Lactobacillus rhamnosus GG versus placebo for acute gastroenteritis in children.” New England Journal of Medicine 379.21 (2018): 2002-2014.

Is allergy testing done in a way to reflect regional allergens?


Both indoor (pets, mites) and outdoor (pollens, molds) inhalant allergens vary regionally so allergists should factor in regional differences when performing allergen tests. For example, an allergist should use regionally dominant allergens such as local grasses when testing allergens such as grass pollens. However, the reality is allergies tend to be both under-diagnosed and under-treated. Allergic individuals can better monitor their symptoms by looking up regional Pollen Bulletins such as those available at the National Allergy Bureau in the US, NAB Pollen Counts | AAAAI. Doing so may help them provide crucial information to the allergists they consult with.

Climate, geography, temperature, vegetation impose tremendous variations in both the number and nature of pollens in different places and some of the resulting sensitization patterns can even appear counter-intuitive from a strictly abundance-oriented viewpoint. For example, even though rural areas have higher pollen counts, they tend to have lower pollen sensitization rates (1).

Climate change is also predicted to considerably impact allergen exposure. For example, oak trees in Spain are predicted to pollinate one month earlier due to climate change (2) while plants are also expected to simply produce more pollen as a result (3, 4, 5).

Uncovering the tick-red meat allergy link aka Alpha-gal allergy – Wikipedia is a poster child for why paying attention to regional reactivity patterns can be crucial.

  • In the mid to late 2000s, reports of a mysterious new pattern of IgE antibody-mediated hypersensitivity reactions to red meat emerged in parts of southeastern US.
  • Simultaneously, reports emerged of hypersensitivity and even anaphylactic IgE responses in cancer patients in Arkansas, Missouri, North Carolina, Tennessee and Virginia in response to Cetuximab – Wikipedia, which is a Monoclonal antibody – Wikipedia that inhibits the epidermal growth factor receptor and is used to treat a variety of cancers.

Allergologists at the University of Virginia Health System’s Allergy Division found the target of these IgE antibodies to be galactose-a-1,3-galactose (-gal), a carbohydrate usually found in red meat (6).

Turns out cetuximab -gal residues were very similar to those found in mammalian meats such as beef, pork, lamb, cat and dog but which are absent in non-mammalian meats such as chicken, fish and turkey.

Reaction time was the main difference between cetuximab and red meat allergy. While allergic reactions to cetuximab typically appear within 20 minutes of drug administration, reaction (intense itching, swelling, hives) to red meat (beef, lamb, pork) typically occurs 2 to 6 hours after ingestion. This difference is assumed to reflect the time it takes for the -gal-bearing antigens to appear in the circulation after eating meat.

Humans don’t synthesize -gal so having anti–gal IgE antibodies isn’t surprising at the outset. However, why did only some patients in only specific southeastern US states have such pre-existing IgE antibodies? After all, mammalian meat is consumed all over the US.

The distribution pattern of pre-existing circulating anti–gal IgE antibodies suggested a link to some type of local trigger in southeastern US states. That link turned out to be the lone star tick (Amblyomma americanum).

  • While trying to uncover the connection between cetuximab and red meat hypersensitivity reactions, three members of this UVA team itself developed red meat allergy and each of them distinctly recalled being bitten by ticks some weeks or months before they exhibited allergy symptoms (7).
  • Providentially, serum samples from these individuals were available both before and after their tick bite experience. Testing them revealed 4 to 10-fold higher anti–gal IgE antibodies in the post-tick bite serum samples. This naturally opened up a possibly fertile line of enquiry.
  • When cetuximab-allergic patients were likewise asked about their experience of tick bites, most of those with delayed anaphylaxis recalled recent bites of either adult or larval ticks.
  • A comparison of US lone star tick distribution showed it overlapped with both cetuximab sensitivity and red meat allergy (below from 8).

In 2007, studies all the way in Australia also suggested a link between mammalian meat allergy and tick bites after researchers there described 25 adults who developed red meat allergy after tick bites (9). In the years since, red meat allergy reports have emerged in other countries as well and the ticks involved turn out to be diverse (below from 10, 11).

Paying attention to regional patterns of reactivities was thus key in uncovering the link between allergy to drug (cetuximab) and to red meat on the one hand and history of tick bite(s) on the other hand (below from 12).

While the tick bite-red meat allergy link has now been established, several questions still remain unanswered,

  • Only a few of those who experience tick bites develop red meat allergy. What is different about such individuals? Genetic polymorphism and/or microbiota difference could explain why they make an IgE response to -gal. Either factor could potentially engender a predisposition for making anti–gal IgE antibody response while the tick bite(s) might be acting as a catalyst that somehow drives the manifestation of the actual IgE response.
  • How does the tick bite drive anti–gal IgE antibody response? Something tick-derived in tick saliva? Something mammal-derived in tick saliva from its previous blood meal? Some microorganism present in the tick?

But that’s the way it goes with science. Answering one question leads to other questions.


1. Burr, M. L., et al. “Pollen counts in relation to the prevalence of allergic rhinoconjunctivitis, asthma and atopic eczema in the International Study of Asthma and Allergies in Childhood (ISAAC).” Clinical & Experimental Allergy 33.12 (2003): 1675-1680. Pollen counts in relation to the prevalence of allergic rhinoconjunctivitis, asthma and atopic eczema in the International Study of Asthma and Allergies in Childhood (ISAAC) – Burr – 2003 – Clinical &amp; Experimental Allergy – Wiley Online Library

2. García-Mozo, Herminia, et al. “Quercus pollen season dynamics in the Iberian Peninsula: response to meteorological parameters and possible consequences of climate change.” Annals of Agricultural and Environmental Medicine 13.2 (2006): 209.…

3. Wayne, Peter, et al. “Production of allergenic pollen by ragweed (Ambrosia artemisiifolia L.) is increased in CO2-enriched atmospheres.” Annals of Allergy, Asthma & Immunology 88.3 (2002): 279-282.…

4. Barnes, Charles S. “Impact of Climate Change on Pollen and Respiratory Disease.” Current allergy and asthma reports 18.11 (2018): 59.

5. Demain, Jeffrey G. “Climate change and the impact on respiratory and allergic disease: 2018.” Current allergy and asthma reports 18.4 (2018): 22.

6. Commins, Scott P., et al. “Delayed anaphylaxis, angioedema, or urticaria after consumption of red meat in patients with IgE antibodies specific for galactose-α-1, 3-galactose.” Journal of Allergy and Clinical Immunology 123.2 (2009): 426-433.…

7. Steinke, John W., Thomas AE Platts-Mills, and Scott P. Commins. “The alpha-gal story: lessons learned from connecting the dots.” Journal of Allergy and Clinical Immunology 135.3 (2015): 589-596.…



10. Cabezas-Cruz, Alejandro, et al. “Regulation of the immune response to α-Gal and vector-borne diseases.” Trends in Parasitology 31.10 (2015): 470-476.…

11. van Nunen, Sheryl A. “Tick-induced allergies: mammalian meat allergy and tick anaphylaxis.” The Medical Journal of Australia 208.7 (2018): 316-321.…

12. Fischer, Jörg, Amir S. Yazdi, and Tilo Biedermann. “Clinical spectrum of α-Gal syndrome: from immediate-type to delayed immediate-type reactions to mammalian innards and meat.” Allergo journal international 25.2 (2016): 55-62. Clinical spectrum of α-Gal syndrome: from immediate-type to delayed immediate-type reactions to mammalian innards and meat

What are alternative therapies for minimizing or getting rid of allergies other than immunotherapy (a.k.a allergy shots)?


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There is as yet no known medical cure for allergies. Immunotherapy in the form of allergy shots offers the promise of a cure but this is still very much in the development phase.

All other treatments manage allergy symptoms and do not mediate cure.

Antihistamines and corticosteroids (inhaled or topical) are mainstays for treating most allergy symptoms.

  • Antihistamines, short- and long-acting bronchodilators such 2-agonists and anticholinergics as well as inhaled corticosteroids are used in the case of asthma.
  • In addition to antihistamines and corticosteroids, mast cell-blocking agents such as sodium cromoglicate and nedocromil sodium may be sometimes prescribed for hay fever (allergic rhinitis) and for allergic conjunctivitis.
  • Nasal decongestants and topical steroids are prescribed for sinusitis.
  • Topical steroids are also mainstays for treating symptoms of atopic dermatitis (eczema) and contact dermatitis (hypersensitivity).
  • Avoidance is the main approach for dealing with food and drug allergies as well as allergies to widely prevalent modern products such as latex and as much as possible even to aeroallergens such as pollen and other environmental allergens such as dust mites.
  • Anaphylaxis or life-threatening acute allergic reaction requires immediate management in the form of intramuscular epinephrine as well as antihistamine and hydrocortisone.

What potential Alzheimer’s treatments have been successful in mice?

Potential Alzheimer’s treatments being successful in mice presumes they too get Alzheimer’s even though there’s little to no supporting evidence whatsoever for such a supposition. A dead end and that would be that, right? Not so since neurological disease research has also fallen prey to the same affliction that these days bedevils the study of so many other human diseases, namely, the herd mentality to contrive highly artificial animal models to study some biological phenomena, all while contending they’re reasonable stand-ins for those observed in their human disease counterpart.

Mouse models are most common mainly because they currently have available the most well developed cellular and molecular biology tools. Accordingly, the lure of animal models of human diseases rising to a fever pitch, by the late 1990s a bunch of genetically engineered mouse strains were created purporting to model human Alzheimer’s (below from 1, 2).

Various transgenic mouse strains that over-express proteins implicated in the amyloid hypothesis (accumulation of abnormally folded amyloid-beta protein) were predictable choices because this dominant Alzheimer’s hypothesis has for >20 years implicated such proteins as disease targets (3, 4, 5).

According to a 2014 review (5), pharmacological and lesioned animal models exist in addition to genetically engineered transgenic ones; since cholinergic neurons are seen to preferentially degenerate in Alzheimer’s, a scopolamine-induced amnesia model is used to block cholinergic receptors to induce cognitive impairment, while lesion models entail producing a variety of surgical lesions in an attempt to mimic the kind of damage seen in Alzheimer’s.

Many experimental treatments proved successful in these various mouse models. However, knowing that they worked in mouse models is of little value in and of itself if such results don’t translate to humans and that’s where the results are so abysmal, the numbers don’t speak, they shout.

  • A shocking total of 99.6% of potential Alzheimer’s cures failed in clinical trials by 2014 (6).
  • Of 244 promising drug candidates identified using preclinical animal models that went into Alzheimer’s clinical trials between 2002 and 2012, only one was approved; a paltry success rate of 0.4% even as 65.6% (145 of 221) trials registered between 2002 and 2012 studied the amyloid-beta protein target (7).

Why has translation of promising preclinical Alzheimer’s data failed so spectacularly? Not just the proverbial many a slip between cup and lip between preclinical models and human Alzheimer’s but rather a yawning chasm.

  • Cost for one thing. Transgenic mouse strains can be eye-poppingly expensive, with each mouse selling for >$500 in the case of a particular amyloid-beta transgenic mouse strain (8). Few labs anywhere in the world have the kind of funding that would allow them to purchase, house and test the necessary numbers of mice per experimental group, let alone perform the number of repeats necessary to yield statistically reliable data.
  • Transgenic animals have a lot of problematic issues that tend to get glossed over, especially by those not in the know (2).
    • In the case of human Alzheimer’s, genes suspected of being related to the condition are artificially introduced into a mouse embryo under the control of a specific promoter. However, the molecular techniques used to create such transgenic animals had no control over where and how many copies of the gene got inserted, how the inserted gene got transcribed or translated, what kinds of post-translational modifications the ensuing protein might undergo, to mention just a few of the more obvious variables that remain out of control.
    • The promoter chosen to drive a transgene’s expression has an outsized influence on which tissues would express it, how abundantly and when.
    • Such issues are amplified in the case of Alzheimer’s transgenic animal models because in each case, a ‘foreign’ human gene is being forcibly expressed in mouse tissues. This may trigger any number of unpredictable regulatory or defense processes in the cells in which the transgene got inserted.
  • Transgenic mouse models typically attempt to mimic familial Alzheimer’s, which represents <1% of all Alzheimer’s (4, 9).
  • Transgenic animals have so far failed to recapitulate many of the cardinal features of human Alzheimer’s; not the time of initiation of atrophy nor its site nor its extent nor the specifics of the pathology.

Epitaph for mouse models of Alzheimer’s should rightfully read, ‘Too much pain for little or no gain’.


1. Emilien, Gérard, et al. “Alzheimer disease: mouse models pave the way for therapeutic opportunities.” Archives of neurology 57.2 (2000): 176-181. Alzheimer Disease

2. Cavanaugh, Sarah E., John J. Pippin, and Neal D. Barnard. “Animal models of Alzheimer disease: historical pitfalls and a path forward.” ALTEX-Alternatives to animal experimentation 31.3 (2014): 279-302.…

3. Bales, Kelly R. “The value and limitations of transgenic mouse models used in drug discovery for Alzheimer’s disease: an update.” Expert opinion on drug discovery 7.4 (2012): 281-297.

4. LaFerla, Frank M., and Kim N. Green. “Animal models of Alzheimer disease.” Cold Spring Harbor perspectives in medicine (2012): a006320. http://perspectivesinmedicine.cs…

5. McGonigle, Paul. “Animal models of CNS disorders.” Biochemical pharmacology 87.1 (2014): 140-149.

6. Alzheimer’s R&D suffers as trial failure rate hits an ‘astounding’ 99.6%

7. Cummings, Jeffrey L., Travis Morstorf, and Kate Zhong. “Alzheimer’s disease drug-development pipeline: few candidates, frequent failures.” Alzheimer’s research & therapy 6.4 (2014): 37. Alzheimer’s disease drug-development pipeline: few candidates, frequent failures

8. Green, Susan Bridgwood. “Can animal data translate to innovations necessary for a new era of patient-centred and individualised healthcare? Bias in preclinical animal research.” BMC medical ethics 16.1 (2015): 53. Can animal data translate to innovations necessary for a new era of patient-centred and individualised healthcare? Bias in preclinical animal research

9. Laurijssens, Bart, Fabienne Aujard, and Anisur Rahman. “Animal models of Alzheimer’s disease and drug development.” Drug Discovery Today: Technologies 10.3 (2013): e319-e327.…