Has there ever been an HIV positive organ transplanted into HIV negative recipient?



Medical literature reports several examples of inadvertent HIV transmission through organ transplant during the 1980s, which have dwindled to individual case reports in recent years.

A 1993 review summarized English language reports of a total of 75 cases of HIV infection in HIV-negative organ recipients (1). These included 50 cases for kidney, 13 for liver, 6 for heart, 4 for bone and 1 each for pancreas and skin. All but 14 of these cases occurred before routine donor screening for anti-HIV antibody began in 1985. Thus, during the 1980s, several cases of HIV transmission through organ transplantation were reported with the last such case in 1989 (2).

That long streak was broken by a handful of more recent reports,

  • A 2007 HIV transmission through solid organ transplant involved a kidney transplant in Italy (3).
  • A 2008 with a liver transplant recipient in the US who became both HIV and HVC (Hepatitis C) positive 10 months post-transplant (4).
  • A 2009 kidney transplant case in the US (5), who became HIV-positive one year later.

Detailed testing attributed source to donor tissue in all three cases.

Unlike mandatory screening for blood where HIV infection is tested by presence of anti-HIV antibodies as well as by the far more sensitive nucleic acid amplification testing (NAT), screening policies for solid organs are not so standardized and usually include only anti-HIV antibody testing (6).

Another 2007 case reported in 2012 (7), this one from India, exemplifies the drawback of screening using antibody testing alone. Though the recipient and donor, her sister, were both confirmed HIV negative by antibody testing at the time of the transplant, both were found infected 9 months post-transplant. Further testing and retrospective analysis of family history revealed that at the time of the donation, the donor was in the ‘window period‘ of infection, having acquired the infection from her husband. In this case, ‘window period‘ refers to the time between initial infection and detection of circulating anti-HIV antibodies. OTOH, window between initial infection and a positive NAT test is presumed to be much shorter (8).


1. Simonds, Robert J. “HIV transmission by organ and tissue transplantation.” Aids 7 (1993): S35-38.

2. Quarto, M., et al. “HIV transmission through kidney transplantation from a living related donor.” The New England journal of medicine 320.26 (1989): 1754.

3. Borchi, B., et al. “Case report: HIV infection from a kidney transplant.” Transplantation proceedings. Vol. 42. No. 6. Elsevier, 2010. https://www.researchgate.net/pro…

4. Ahn, Joseph, and Stanley M. Cohen. “Transmission of human immunodeficiency virus and hepatitis C virus through liver transplantation.” Liver Transplantation 14.11 (2008): 1603-1608.

5. Centers for Disease Control and Prevention (CDC. “HIV transmitted from a living organ donor–New York City, 2009.” MMWR. Morbidity and mortality weekly report 60.10 (2011): 297. https://www.cdc.gov/mmwr/pdf/wk/…

6. Wispelwey, Bram P., Ari Z. Zivotofsky, and Alan B. Jotkowitz. “The transplantation of solid organs from HIV-positive donors to HIV-negative recipients: ethical implications.” Journal of medical ethics 41.5 (2015): 367-370.

7. Mukhopadhyay, P., et al. “Transmission of human immunodeficiency virus infection by renal transplantation.” Indian journal of nephrology 22.2 (2012): 133.

8. Phelps, Ruby, et al. “Window‐period human immunodeficiency virus transmission to two recipients by an adolescent blood donor.” Transfusion 44.6 (2004): 929-933.



How long could your innate immune system sustain on its own?


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As of 2017, at least 150 different Primary immunodeficiency – Wikipedia (PIDs) have been reported in the literature with mutations in >120 genes implicated therein (1).

For the innate immune system to sustain on its own means having a non-functioning adaptive immune system, i.e., to have missing or non-functioning T and/or B cells.

Rather than our innate immune system being able to sustain health in the absence of the adaptive immune system, famous examples of the so-called Bubble boy disease or Severe combined immunodeficiency – Wikipedia (SCID) instead show that the condition is instead unsustainable, at least without intensive, expensive, high-tech medical intervention. Until fairly recently, despite such intensive care, a famous example such as David Vetter – Wikipedia still died by 12 years of age.

T-B-SCID (missing/non-functioning T and B cells) is one of the most severe PIDs (see below from 2 and 3)

  • Inherited as either X-linked Recessive or Autosomal Recessive, depending on whether or not the gene(s) involved is/are on the X chromosome.
  • Its hallmarks are failure to thrive, and recurrent, serious and/or life-threatening infections.

As with many other immunodeficiencies, the degree of severity of the T-B-SCID is directly related to

  • Nature of the underlying genetic defect(s): degree of deletion or nature of mutation (Muller’s morphs – Wikipedia).
  • Degree of feto-maternal chimerism (Chimera (genetics) – Wikipedia), i.e., degree to which functional T and/or B cells from the mother transferred to the baby in utero are able to survive and function, and for how long.
  • Unpredictable gene-environment interactions.

Such unpredictable mitigating factors being in play means even though without intensive medical intervention, severe T-B-SCIDs are nearly always fatal, it cannot always be predicted when the condition tips past the point of no return. Consider for example an Omenn syndrome – Wikipedia patient who survived for 6 years without Hematopoietic stem cell transplantation – Wikipedia (HSCT) and yet was found to carry Missense mutation – Wikipedia in both alleles of the RAG1 (Recombination-activating gene – Wikipedia), one of two genes necessary for T and B cell development (4). Patient turned out to have maternal-derived circulating T cells.

However, rather than a savior in all instances, such feto-maternal chimerism in T-B-SCIDs can also turn out to be quite the double-edged sword since the maternal-derived cells could just as often end up attacking the recipient infant’s cells and tissues, a form of Graft-versus-host disease – Wikipedia (GVHD).

Robert A. Good – Wikipedia, considered one of the founders of modern immunology, pioneered the use of bone marrow transplants for treating PIDs such as T-B-SCID. Better known these days as HSCT, it’s the treatment of choice while Gene therapy – Wikipedia is also being intensively explored. While back in 1977, HSCT was successful in only 14 of 69 transplanted patients (~20%) (5), by 2004, this had climbed to 63 to 84% (6). However, HSCT is still no panacea since patients remain at risk for infection complications and Graft-versus-host disease – Wikipedia (GVHD) (see below from 3).


1. Le Deist, Françoise, et al. “Combined T-and B-Cell Immunodeficiencies.” Primary immunodeficiency diseases. Springer Berlin Heidelberg, 2017. 83-182. http://content.schweitzer-online…

2. http://www.newbornscreening.info…

3. Buckley, Rebecca H. “A historical review of bone marrow transplantation for immunodeficiencies.” Journal of allergy and clinical immunology 113.4 (2004): 793.

4. Kumaki, Satoru, et al. “Identification of anti–herpes simplex virus antibody–producing B cells in a patient with an atypical RAG1 immunodeficiency.” Blood 98.5 (2001): 1464-1468. http://www.bloodjournal.org/cont…

5. Bortin, Mortimer M., and Alfred A. Rimm. “Severe combined immunodeficiency disease: characterization of the disease and results of transplantation.” Jama 238.7 (1977): 591-600.

6. Buckley, Rebecca H. “Molecular defects in human severe combined immunodeficiency and approaches to immune reconstitution.” Annu. Rev. Immunol. 22 (2004): 625-655. https://www.researchgate.net/pro…


Can I live to or past 80 with HIV?


As HIV Rx improves, it may be possible for an HIV-positive person to survive for decades on Rx (treatment). However, we don’t yet have data to say whether or not someone diagnosed with HIV in their 20s will be able to live past 80. Currently, life expectancy for HIV-positive depends on whether or not they take combination Antiretroviral therapy or cART (Management of HIV/AIDS – Wikipedia) every day for life. This in turn depends on availability, affordability and access to these drugs.

Clearly, in places like the USA, with better access to long-term combination ART, it’s possible for HIV patients to live longer. For example, data from the US CDC showed steadily increasing death rate changes for HIV-positive in different age groups shifting towards older age groups, meaning they’re living longer (1, 2). A 2013 analysis of US HIV-positive mortality trends suggested that life expectancy for those diagnosed with HIV at 20 years of age increased from ~36 years in 2000 – 2002 to ~51 years by 2006 – 2007 (3).

A 2017 Meta-analysis – Wikipedia (4) found

  • No gender differences in life expectancy among those on cART.
  • Unsurprisingly, life expectancy of 20 year olds diagnosed with HIV was better in high income countries.
  • However, life expectancy of those on cART still hasn’t reached that of the general population, even in high income countries.

Another 2017 analysis on 88504 patients from 18 European countries plus North America (see below from 5) found estimated life expectancy for 20 year old HIV-positives starting ART in 2008-2010 had increased to ~63 years in women and ~66 years in men in North America. However, this is still lower than estimated life expectancy increases to ~68 years in European HIV-positive women and men as well as general US life expectancies of 82 and 78 years, respectively, for women and men.

Even when HIV is well-controlled through daily ART, problem is long-term consequences of the infection in the form of cancer or liver disease or accelerated aging remain tangible risk factors (6). While there are a handful of examples of patients ‘cured’ of HIV (7), mainly following either stem cell transplantation or getting started on very powerful ART very shortly after getting infected with HIV, main obstacle to its complete elimination from the body is Virus latency – Wikipedia, i.e., virus is still present in a dormant state in the body.


1. https://www.cdc.gov/hiv/pdf/stat…

2. Libman, H. “Will You Still Treat Me When I’m 64? Care of the Older Adult With HIV Infection.” Topics in antiviral medicine 23.2 (2014): 97-103. http://www.iasusa.org/sites/defa…)

3. Samji, Hasina, et al. “Closing the gap: increases in life expectancy among treated HIV-positive individuals in the United States and Canada.” PloS one 8.12 (2013): e81355. http://journals.plos.org/plosone…

4. Teeraananchai, S., et al. “Life expectancy of HIV‐positive people after starting combination antiretroviral therapy: a meta‐analysis.” HIV medicine 18.4 (2017): 256-266.

5. Antiretroviral Therapy Cohort Collaboration. “Survival of HIV-positive patients starting antiretroviral therapy between 1996 and 2013: a collaborative analysis of cohort studies.” The Lancet HIV (2017). http://ac.els-cdn.com/S235230181…

6. Taddei, Tamar H., Vincent Lo Re, and Amy C. Justice. “HIV, Aging, and Viral Coinfections: Taking the Long View.” Current HIV/AIDS Reports 13.5 (2016): 269-278.

7. Tirumalai Kamala’s answer to What is the current state of the HIV cure?


Which drug is used to treat chronic hepatitis B?



Current standard of care for chronic Hepatitis B (HBV) consists of Pegylated interferon – Wikipedia (Type I Interferon or IFN-alpha-2a) or nucleos(t)ide analogs (NA). These two types of treatment (Rx) have different administration routes and rationale (1),

Further, assessing how well these Rx work is far from straightforward. This answer outlines

  • Why assessment of efficacy of chronic HBV Rx is difficult.
  • Standard Rx (as of 2017) for chronic HBV Rx.

Why assessment of efficacy of chronic HBV Rx is difficult

At present chronic HBV infection has no cure.

Rather than a monochrome disease with a singular, inexorable outcome, chronic Hepatitis B (HBV) has distinct phases. However, not all patients appear to go through each one of them and neither have the anti-HBV immune responses during each phase been fully characterized yet (2).

The main goal of current HBV Rx is to prevent or mitigate risk of cirrhosis and liver cancer (hepatocellular carcinoma), and decision to treat/not and if yes, then with what, is made on the basis of clinical and lab assessment of individual patient’s HBV phase (see below from 1).

HBV disease pattern also depends on

  • Whether the patient has other liver infections such as Hepatitis C or D, HIV, has autoimmune or metabolic liver disease or is alcoholic.
  • This picture is complicated by the fact that
    • Though current Rx is considered safe and effective, long-term use does carry risk of complications (2).
    • Patient’s individual HBV gentoype that can range from A to I (9 gentoypes plus sub-genotypes), which can influence both response to Rx as well as risk for developing resistance (1).

While a detailed meta-analysis of 42 studies with a combined 62731 patients revealed a modest Rx benefit for chronic HBV patients with advanced fibrosis or cirrhosis (3), Rx data are on the whole poor for a couple of reasons (2).

  • Chronic HBV infection usually progresses slowly, with its worst outcomes (cirrhosis and cancer) usually manifesting decades later.
  • Clear benefit of therapy requires a very large study that
    • Should include a control group that does not get any treatment.
    • Is followed for many years in order to allow time for worst outcomes to develop.
  • Obviously, such a study would be both unethical and impractical.

Standard Rx (as of 2017) for chronic HBV Rx

Thus far in 2017, the European Association for the Study of the Liver (EASL) has published a thorough and detailed guideline for how to manage HBV (see below from 1).


1. European Association for the Study of the Liver. “EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection.” Journal of Hepatology (2017). http://ac.els-cdn.com/S016882781…

2. Ghany, Marc G. “Current Treatment Guidelines Of Chronic Hepatitis B: The Role Of Nucleos (t) ide Analogues And Peginterferon.” Best Practice & Research Clinical Gastroenterology (2017).

3. Lok, Anna SF, et al. “Antiviral therapy for chronic hepatitis B viral infection in adults: A systematic review and meta‐analysis.” Hepatology 63.1 (2016): 284-306. http://onlinelibrary.wiley.com/d…


How far away should I sit from someone who might have Norovirus?


Unfortunately, just sitting far enough away from someone who might have Norovirus isn’t sufficient to stave off getting infected with it. This is not only because it’s highly contagious but also because of

  • How Norovirus spreads: Not just directly through fecal-oral transmission but also from eating and drinking contaminated food and water, handling contaminated surfaces and objects (fomites) followed by hand-to-mouth contact, and via ingestion of aerosolized particles (1), a Norovirus property unique among GI tract pathogens (2).
    • For example, samples from mantels and light fittings 1.5 meters above the ground during a hotel outbreak in England were positive for Norovirus (3), suggesting source to be aerosolized particles released from vomit.
  • How long Norovirus can stay infectious in the environment (4).

These two factors help explain why it can spread so fast in places where people spend time in close proximity to one another, such as on cruise ships, hospitals and nursing homes.

So far, only genetic fortune in the form of a single nucleotide mutation (G428A) in the FUT 2 gene (FUT2 – Wikipedia) on chromosome 19 provides strong protection against Norovirus (5, 6). This mutation is present in ~20% of whites.

According to the US CDC (7),

  • Norovirus outbreaks ‘can occur anywhere people gather or food is served‘.
  • Cruise ship outbreaks account for only ~1% of all reported Norovirus outbreaks with 70% caused by infected food workers.

Norovirus patients usually vomit and have diarrhea. Several reasons for why infected Norovirus patients are so contagious,

  • While they shed billions of virions in their vomit and stool, ‘it only takes as few as 18 viral particles to infect another person‘ (7, 8, 9, 10).
  • People can spread Norovirus both even before feeling sick and as long as two weeks after starting to feel better (11).
  • Norovirus on a variety of surfaces such as ceramic plates, drinking glasses, stainless steel forks is more resistant to traditional decontamination methods (12).
  • Norovirus can remain infectious (13) on reusable grocery bags for as long as 2 weeks (14) and diaper changing stations (15).

Norovirus on ceramic plates, drinking glasses, stainless steel forks is more resistant to strong disinfectants compared to other microbes: One study (12) assessed capacity of restaurant-style cleaning procedures to eliminate Norovirus. In the US, as per the FDA Food Code (13), restaurants and other food service establishments are required to use disinfectant procedures that can reduce microbial load on tableware and food preparation utensils by a minimum of 5 logs.

The authors smeared ceramic plates, drinking glasses and stainless steel forks with mouse Norovirus (MNV-1)-containing cream cheese and reduced-fat milk. Solutions containing powerful disinfectants such as sodium hypochlorite (chlorine) or quaternary ammonium (QAC) (12) reduced Norovirus by a maximum of only 3 logs.

Norovirus on a reusable grocery bag can be infectious without person-to-person contact and is detectable on it even 2 weeks later: Environmental sleuthing (see below from 14) traced the source of a Norovirus outbreak in Oregon to a reusable grocery bag. In this case, 13 to 14 year old soccer players had all fallen ill less than 48 hours after they’d traveled together out of town for a week-end tournament. First to fall ill on Saturday night was a girl (the index case) who moved into the room of one of the parent chaperones but these two then went home early Sunday with no further contact with the other players. Yet, seven other players fell ill over the next 48 hours. How?

Interviews revealed most of the ones who got ill ate cookies at a Sunday lunch, cookies that in turn had been left behind in a reusable grocery bag in the empty hotel room of the first girl who fell ill. Turns out this girl had been very ill in the hotel bathroom and likely spread Norovirus aerosol that landed everywhere including the reusable grocery bag hanging in the room. Scientists found the bag positive for Norovirus even two weeks later. Thus, this was a case of Norovirus transmission without person-to-person contact.

Norovirus from improperly disinfected diaper-changing station can cause infections not only to those who came in direct contact with it but to others in the same workplace as well: In another Oregon outbreak (see below from 15), 12 of 16 auto-dealership employees fell ill after a staff meeting. In this case, the culprit wasn’t among the take out sandwiches but rather an unwelcome ‘gift’ left behind by a customer whose toddler ‘sprayed’ the dealership’s sole women’s restroom with diarrhea a mere 15 minutes before the staff meeting lunch began.

‘When staff at the auto dealership were interviewed, we learned of an incident that occurred approximately 15 minutes before the luncheon began. A female staff member (employee A) had entered the sole women’s restroom at the dealership to discover a customer managing a toddler with diarrhea by holding the incontinent child over the trash receptacle while the toddler was (in the staff member’s words) “spraying.” The wall-mounted diaper changing station (brand X) was deployed and was visibly soiled with fecal material, as were the floor, walls, and trash can. The child’s mother left the mess for employee A, who attempted to clean up with dry paper towels. No gloves or disinfectants were used, but employee A reported subsequently washing her hands with soap and water.

Meanwhile, employee B had gone to pick up the food for the meeting. Immediately after cleaning the restroom, employee A opened the door for employee B when the latter returned with the food. Employee A was the first to take one of the un-wrapped sandwiches off the platter. Four of 5 female cases reported eating a sandwich, as did 6 of 7 male cases.

All 5 female employees working that day became ill; all reported use of the restroom after the diarrheal incident. Seven of 11 male employees (64%) became ill — not a statistically significantly different rate. None of the men entered the ladies’ rest-room.’

Thus in this case, after getting directly exposed to fecal material left behind on an improperly disinfected diaper-changing station by a sick toddler, female employees sufficiently contaminated their wider work environment, including uncovered sandwiches, to cause their male colleagues to fall sick as well.

Meanwhile, government policies increase, not decrease, chances of sick workers transmitting Norovirus.

  • For example, ‘10 [US] states have passed laws prohibiting local governments from establishing sick-leave laws‘ (16).
  • A US CDC survey of 491 restaurant workers in 2011 found a fifth (20%) worked while sick with vomiting or diarrhea (17).
  • The US CDC has also found that sick line-cooks can spread Norovirus by coming to work sick (18).


1. Hall, Aron J., et al. “Updated norovirus outbreak management and disease prevention guidelines.” MMWR Recomm Rep 60.3 (2011). https://www.cdc.gov/mmwr/pdf/rr/…

2. Hall, Aron J. “Noroviruses: the perfect human pathogens?.” Journal of Infectious Diseases 205.11 (2012): 1622-1624. https://www.researchgate.net/pro…

3. Cheesbrough, J. S., et al. “Widespread environmental contamination with Norwalk-like viruses (NLV) detected in a prolonged hotel outbreak of gastroenteritis.” Epidemiology and infection 125.01 (2000): 93-98. https://www.ncbi.nlm.nih.gov/pmc…

4. Lopman, Ben, et al. “Environmental transmission of norovirus gastroenteritis.” Current opinion in virology 2.1 (2012): 96-102.

5. Lindesmith, Lisa, et al. “Human susceptibility and resistance to Norwalk virus infection.” Nature medicine 9.5 (2003): 548-553. https://www.researchgate.net/pro…

6. Rydell, Gustaf E., et al. “Susceptibility to winter vomiting disease: a sweet matter.” Reviews in medical virology 21.6 (2011): 370-382.

7. Clinical Overview

8. Teunis, Peter FM, et al. “Norwalk virus: how infectious is it?.” Journal of medical virology 80.8 (2008): 1468-1476. https://www.researchgate.net/pro…

9. Atmar, Robert L., et al. “Norwalk virus shedding after experimental human infection.” Emerging infectious diseases 14.10 (2008): 1553. https://pdfs.semanticscholar.org…

10. Aoki, Y., et al. “Duration of norovirus excretion and the longitudinal course of viral load in norovirus-infected elderly patients.” Journal of Hospital Infection 75.1 (2010): 42-46.

11. NBC News, Maggie Fox, January 28, 2013. Norovirus: Why washing your hands isn’t enough

12. Feliciano, Lizanel, et al. “Efficacies of sodium hypochlorite and quaternary ammonium sanitizers for reduction of norovirus and selected bacteria during ware-washing operations.” PLoS One 7.12 (2012): e50273. http://journals.plos.org/plosone…

13. https://www.fda.gov/downloads/fo…

14. Repp, Kimberly K., and William E. Keene. “A point-source norovirus outbreak caused by exposure to fomites.” Journal of Infectious Diseases 205.11 (2012): 1639-1641. https://oup.silverchair-cdn.com/…

15. Repp, Kimberly K., Trevor P. Hostetler, and William E. Keene. “A norovirus outbreak related to contaminated environmental surfaces.” Journal of Infectious Diseases (2013): jit148. https://oup.silverchair-cdn.com/…

16. The Atlantic, Olga Khazan, March 5, 2014. Poor and Hispanic Workers Are Least Likely to Have Sick Days

17. Restaurant Food Handling & Food Safety Practices

18. Norovirus Outbreak Associated with Ill Food-Service Workers — Michigan, January–February 2006


Is there a study to prove that the smallpox vaccine cures smallpox?


Based on a general 18th century observation that farm maids in England, France, Germany, Holland, Italy and Mexico who came in contact and got infected with cowpox appeared resistant to smallpox (1), cowpox, the original smallpox vaccine, was intended to prevent, not cure, smallpox.

Smallpox vaccine in the form of cowpox was first introduced in the mid-to-late 18th – early 19th centuries when little was known about the causes of infectious diseases, certainly long before the discovery of micro-organisms. Since then a variety of vaccines have been used against smallpox including horsepox, and in the 20th century, attentuated (weakened) vaccinia virus and inactivated vaccines. Thus the biggest obstacle in the quest for smallpox vaccine efficacy data is it was eradicated from Europe and North America by mid-20th century and the world over by 1977 without the kind of controlled clinical trial that would now be mandated to evaluate the efficacy of a new vaccine (2), and proof of its efficacy is perforce largely based on historical records. Also important to bear in mind that even in the 18th century, vaccination wasn’t the only game in town.

This answer outlines

  • Historical smallpox prevention measures included not just cowpox vaccination but also smallpox inoculation (variolation), strict case isolation and contact quarantine, all of which contributed to its decline and eventual eradication.
  • Historical smallpox vaccination efforts began long before micro-organisms were discovered, its causative agent identified, and standardized vaccine manufacture, quality control and distribution methods developed.
  • Some historical data on smallpox vaccine efficacy.

Historical Smallpox Prevention Measures Were Many: Not just Cowpox Vaccination But Also Smallpox Inoculation (Variolation), Case Isolation & Contact Quarantine

Inoculation (Variolation – Wikipedia) was the competing approach to try and prevent smallpox outbreaks.

Inoculation is reported to have been long practiced in China, India (see below from 3) and the Ottoman empire.

Consisting of exposure to a mild dose of the disease itself by placing a small piece of infective smallpox material, typically under the skin (2), inoculation was obviously a double-edged sword since it might itself cause disease. Vaccination, OTOH, was based on an entirely different principle, exposure to a related, less dangerous animal disease, cowpox. Though common credit for the cowpox vaccination is usually ascribed to Edward Jenner – Wikipedia, it was apparently first innovated by the English farmer Benjamin Jesty – Wikipedia (4, 5, 6).

Thus, at the time cowpox vaccination appeared on the scene, smallpox inoculation was already being practiced, for example by roving bands of ‘itinerant inoculators‘ (7) in England, Scottish Highlands and Ireland (8). However, historical data suggests vaccination soon overtook inoculation in popularity. The WHO treatise on the subject (2) states,

‘Jenner stated that by 1801 over 100 000 persons had been vaccinated in Great Britain, whereas by 1730, 8 years after the introduction of variolation, less than 1000 people had been variolated in Great Britain and North America’

Cowpox vaccination had several advantages over smallpox variolation (9; see below from 3)

  • Produced a less severe, local inoculation site lesion.
  • Was not communicable to contacts.
  • Greatly reduced risk of disease from vaccination itself unlike inoculation (variolation).

However, all through its history, vaccination wasn’t whole-heartedly accepted by the population at large. For example, a review (10) notes the Medical Officer of Health for Whitechapel in London (11) recorded all the way back in 1859 that**

‘a “deep-rooted” prejudice against vaccination “strongly manifested” in poor neighbourhoods wherever a child had suffered some eruptive disease “syphilitic, eczematous, etc., commonly associated with teething” after vaccination.’

Since smallpox started causing cyclical epidemics from the 16th-17th century onward throughout Europe, some as frequent as every 2 years, with death rates ranging in the tens of thousands during each cycle, affected communities evolved rigorous preventive measures, consisting of prompt detection and expedient isolation of cases and quarantine of their contacts, efforts based on the pioneering insights of British physician John Haygarth – Wikipedia in 1793.

Haygarth’s original insight for exterminating smallpox from Great Britain consisted of ‘isolation of cases, variolation and a system of rewards and punishments‘ (9). It was so spot-on that almost 200 years later the WHO’s smallpox eradication program consisting of surveillance and containment only slightly altered from it by switching from variolation to limited vaccination and including strict isolation of contacts. This also means smallpox eradication ensued from not just vaccination but also from breaking transmission through strict quarantine.

Inoculation, vaccination, isolation of cases, and quarantine of contacts were thus preventive public health measures brought to bear on smallpox for centuries before it was even known what caused the disease and how it spread (see below from 3).

Historical Smallpox Vaccination Efforts Began Long Before Micro-organisms Were Discovered, Its Causative Agent Identified, And Standardized Vaccine Manufacture, Quality Control & Distribution Methods Developed

After the discovery of micro-organisms in the 19th century, bacteria, bacterial spores, protozoa, many organisms were historically suspected of causing smallpox. Not knowing what precisely caused the disease obviously hobbled rigorous assessment of how inoculation or vaccination prevented it even as smallpox vaccination itself became embedded as a widespread public health measure long before modern good manufacturing, clinical and regulatory practices came into existence.

Today it would be unthinkable to inject a vaccine into humans without rigorous quality control. Consider then that smallpox vaccination had already been in place >100 years before a potency assay was even established for it in the beginning of the 20th century (12). Thus even though smallpox vaccination had been in theory compulsory in the UK for decades by that point* (7, 10, 13), ‘the vaccinator had at best a very rough idea of the quantity of active material in the vaccine‘ (12) One reviewer estimates that 19th century smallpox vaccines may have been cowpox, horsepox or even attentuated smallpox (9).

So many caveats notwithstanding, smallpox vaccination as popularized by Jenner was so successful at bringing down smallpox mortality for several decades that many countries soon made smallpox vaccination, usually of infants, compulsory: Bavaria in 1807, Denmark in 1810, Norway in 1811, Bohemia and Russia in 1812, Sweden in 1816, Hanover in 1821, Great Britain in 1853 and France in 1902 (2). Enforcing such laws was however decidedly problematic since standardized methods for large-scale production and distribution of vaccine were then non-existent.

Thus, even though untold numbers of people got inoculated (variolated) or vaccinated against smallpox the world over for > a century, this complicated history means it isn’t possible to perform meta-analyses of well-controlled, rigorously collected scientific clinical trials on smallpox vaccine efficacy. Such data simply doesn’t exist.

  • Historical records of groups of vaccinated and unvaccinated individuals aren’t easy to interpret.
  • What did the vaccinated individuals actually get? Cowpox, smallpox itself, a mix of the two, a mix containing some cowpox with all kinds of other microbes, mainly bacteria, mixed in it? Were they vaccinated or variolated?
  • Lack of standardized vaccination method and doses meant different individuals got different kinds of injections and material, i.e., different routes and doses, two important variables we now know greatly influence the strength and quality of ensuing immunity.

Some Compelling Historical Data On Smallpox Vaccine Efficacy

Even with the many caveats to historical smallpox vaccination data, several compelling examples demonstrate its unmistakable efficacy.

Some of the most robust historical statistical data for smallpox comes from Sweden which began smallpox vaccination late in 1801, making it compulsory in 1816. In the 18th century, Sweden used to have major smallpox epidemics with 3 to 7000 smallpox deaths per million every 5 years or so. The disease was also endemic meaning an average of 6 to 800 smallpox deaths per million as a matter of course. However, from about 1810, mortality rates declined steeply. In 1822, 6 years after smallpox vaccination was made compulsory, smallpox deaths per million had declined to single digits, i.e., a 100-fold reduction. Even though death rates rose slightly and epidemics recurred in later decades of the 19th century, they occurred at much lower frequency and at a fraction of pre-vaccination amplitude (see below from 2).

Lymph that the Empress of Russia obtained from Jenner in 1801 was maintained by arm-to-arm vaccination for >60 years. Infants aged 7 to 8 days at the St. Petersburg Foundling Hospital were vaccinated with this lymph until 1867 when the state switched to vaccines from cows. Compulsory registration of these infants until the age of 25 years meant another historical record with which to assess vaccine efficacy. St. Petersburg had 17 smallpox epidemics between 1826 and 1846. However, out of 15000 foundlings, only 34 (0.23%) got smallpox with only 1 fatality (2).

After Prussia instituted compulsory smallpox vaccination of military recruits in 1833, smallpox deaths fell from 88 per year in 1831 to 1834 to <2 per year for the next 30 years (2).

Prussia, Bavaria and Wurttemberg made smallpox vaccination and revaccination compulsory in 1874. Smallpox mortality rates declined more steeply in those German states compared to those in Austria which only practiced primary vaccination during the same time period (see below from 2).

A 1902 comparison study in Glasgow, Scotland, provides one of the clearest data sets attesting to smallpox vaccine efficacy (see below from 14).

* ~42000 deaths between 1837 and 1840 after a smallpox epidemic swept across England and Wales resulted in its first Vaccination Act in 1840. This made the vaccine freely available though not mandatory, even as it made inoculation an imprisonable offense.

** Plus ca change, plus c’est la meme chose.


1. Barquet, Nicolau, and Pere Domingo. “Smallpox: the triumph over the most terrible of the ministers of death.” Annals of internal medicine 127.8_Part_1 (1997): 635-642. https://www.researchgate.net/pro…

2. Fenner, Frank, et al. “Smallpox and its eradication.” (1988). http://apps.who.int/iris/bitstre…

3. Fenner, F., et al. “Early efforts at control: variolation, vaccination, and isolation and quarantine.” History of International Public Health 6 (1988): 245-276. http://www.leighainslie.com/bigr…

4. Crookshank, Edgar March. History and pathology of vaccination. Vol. 2. P. Blackiston, 1889.

5. Smith, John R. The speckled monster: smallpox in England, 1670-1970, with particular reference to Essex. Vol. 95. Essex Record Office, 1987.

6. Pead, Patrick J. “Benjamin Jesty: new light in the dawn of vaccination.” The Lancet 362.9401 (2003): 2104-2109. http://www.jesty.org/no_pead_lan…

7. Oxley, Deborah. “‘The seat of death and terror’: urbanization, stunting, and smallpox.” The Economic History Review 56.4 (2003): 623-656.

8. Brunton, Deborah. “Smallpox inoculation and demographic trends in eighteenth-century Scotland.” Medical history 36.04 (1992): 403-429. https://www.ncbi.nlm.nih.gov/pmc…

9. Baxby, Derrick. “Smallpox vaccine: ahead of its time.” Interdisciplinary Science Reviews 26.2 (2001): 125-138.

10. Hardy, Anne. “Smallpox in London: Factors in the Decline of the Disease in the Nineteenth Century.” Medical History 27.02 (1983): 111-138. https://www.ncbi.nlm.nih.gov/pmc…

11. https://dlcs.io/pdf/wellcome/pdf…

12. Minor, Philip D. “Live attenuated vaccines: historical successes and current challenges.” Virology 479 (2015): 379-392. https://www.researchgate.net/pro…

13. Smith, John R. The speckled monster: smallpox in England, 1670-1970, with particular reference to Essex. Vol. 95. Essex Record Office, 1987.

14. McVail, J. C. “Small-Pox in Glasgow—1900-1902.” British medical journal 2.2166 (1902): 40. https://www.ncbi.nlm.nih.gov/pmc…


Why do we develop robust immunity after viral infections, but not bacterial infections?

It’s a truism that strength of immunity depends on many factors such as antigen types and doses, organism’s replicative capacity and evasion strategies, number and types of cells involved, responder’s age and health status, to name a few. Could the type of organism influence the nature and strength of immune response? Sure but if human immunity were as a rule weaker against bacteria and fungi compared to viruses, as this question implies, that would represent a huge open sesame to the former and only humans would have emerged worse off from the ensuing bout.

Certainly, adaptations entail a trade-off but choosing to respond more weakly to entire classes of micro-organisms isn’t a trade-off, it’s more akin to signing one’s own death sentence. After all, micro-organisms mutate at a much faster rate than humans. Thus, the fact that we are still around, all >7 billion of us and counting, suggests human adaptations to evolutionary selection pressures entailed robust immunity against all types of pathogens. What that robust immunity entails differs from organism to organism, not between different classes of organisms.

In case this question implies robust immunity to mean serum antibodies that can transfer protection, this is not the exclusive purview of anti-viral immunity alone but also works against bacteria such as those that cause diphtheria (Corynebacterium diphtheriae – Wikipedia), pertussis (Bordetella pertussis – Wikipedia) and tetanus (Clostridium tetani – Wikipedia).

This answer explains why stronger immune responses to an entire class of micro-organisms such as viruses is unlikely because

  • We aren’t specifically more susceptible to bacterial and fungal infections as our immune systems weaken with age.
  • Not just viruses but all types of microbes from bacteria to a variety of parasites continue to impose selection pressure on us.
  • No single entity within the immune system can perceive an entire organism. This implies evolution proceeds by way of incremental tweaks by human and microbe, the two parties engaged in these evolutionary trade-offs.

We Aren’t More Susceptible To Bacterial & Fungal Infections As We Age

If human immunity to virus is more robust than that to bacteria or fungi, what happens as our immune system weakens with age and Immunosenescence – Wikipedia sets in? Specifically, if ‘we develop robust immunity after viral infections, but not bacterial infections‘, do we become disproportionately more susceptible to the latter as we age, as this question implies? No, rather, the deleterious effects of immunosenescence seem to involve increased susceptibility to infectious diseases per se, not just increased susceptibility to bacteria and fungi but not viruses.

In fact, data from countries like the US suggests immunosenescence represents an equal opportunity vulnerability since it entails impaired ability to control both viruses such as Human cytomegalovirus – Wikipedia (CMV) (1, 2) as well as bacteria such as Streptococcus pneumoniae – Wikipedia (3). Even though pneumonia is common among the elderly, often the trigger remains unknown in ~50% of elderly pneumonia patients even in the US (4). Anybody’s guess if it’s a virus such as influenza or Human respiratory syncytial virus – Wikipedia (RSV), bacteria other than S. pneumoniae or fungus such as Chlamydia pneumoniae. Equal opportunity vulnerability indeed.

Major Human Pathogens Include Not Just Viruses & Bacteria But Also Other Organisms

Both human viral and bacterial pathogens, among others, continue to impose selection pressure (5, 6). Consider two textbook examples, one the bacterium, Vibrio cholerae, and the other the retrovirus, HIV. Cholera remains endemic in the Ganges Delta – Wikipedia of Bangladesh, which has the world’s lowest prevalence of blood group O, probably because it’s associated with an increased risk of severe cholera (7, 8, 9). In the case of HIV, the delta 32 mutation deletes a portion of the CCR5 – Wikipedia gene and renders homozygous carriers resistant to HIV (10, 11). Testament to the central importance of adaptive immunity, specifically T cells, is the fact that the Major histocompatibility complex – Wikipedia (MHC complex) contains more infectious disease susceptibility associations than any other portion of the human genome (5). Major human pathogens include both viruses and bacteria (see below from 5).

Other pathogens too impose selection pressure. One of the most well-known examples is malaria (see table below from 6).

No Single Entity Within The Immune System Can Perceive An Entire Organism

While this question shares no data to support its claim that ‘we develop robust immunity after viral infections, but not bacterial infections‘, it implies that some entity within the human immune system can distinguish viruses from bacteria and fungi. The overarching implication that entire classes of organisms could function as selection units for the immune system to adapt against is inaccurate and cannot be substantiated, and here’s why.

Different cells in the immune system express different kinds of receptors of varying specificity and sensitivity. Those of the Innate immune system – Wikipedia (dendritic cells, macrophages, neutrophils, mast cells, NK cells, Innate lymphoid cells, gamma-delta T cells, etc.) are germline-encoded meaning they stay unchanged within the lifespan of an individual while only those of the Adaptive immune system – Wikipedia (T and B cells) are somatically rearranged, meaning they are derived de novo during the lifespan of each individual. Though this feature vastly expands their range to the order of 10^12 unique receptors each per individual as an estimate, what T and B cell receptors bind are hardly the sizes capable of distinguishing a virus from bacterium or fungus or even host cell-derived material for that matter.

  • A B cell’s antigen is estimated in the range of 25 to 30 amino acids in length while CD4 and CD8 T cell receptors recognize even smaller peptides ranging in length a mere 15-20 to 8-10 amino acids, respectively.
  • Binding larger molecules of varying sizes, derived not just from microbes but also the body’s own breakdown products including dead and dying cells, obviously germ-line encoded receptors too lack the capacity to discern their source.

Thus, no single cell of the immune system can directly differentiate a virus from bacterium or fungus or even allergen for that matter. Instead, different immune cells recognize and bind different bits and pieces of their targets. Thus, be the source of physiological disruption virus, bacteria, fungus, archaea, protist or helminth and so on, varied responses of all these immune cells and their products to varying bits and pieces need to be in sync to neutralize and/or eliminate the source of their individual targets, typically a whole organism.

The beauty as also the mystery of the human immune system is that this process occurs by rote in a healthy body even as no single element within the system can ‘see’ the entirety of the disruptor that sets the process in motion in the first place. This is also why on the one hand, Autoimmunity – Wikipedia, i.e., sustained and deleterious immune attack on one’s own cells and tissues, occurs when the immune system’s not functioning optimally, and why on the other, Cancer immunotherapy – Wikipedia can even be considered a realistic treatment option for tumors. Regardless the trigger, a common set of rules learned over evolutionary time guide the initiation, maintenance, termination and yes, even strength of immune responses, even as no single entity within this system can discern that trigger in its entirety.


1. Pawelec, Graham, et al. “The impact of CMV infection on survival in older humans.” Current opinion in immunology 24.4 (2012): 507-511. https://www.researchgate.net/pro…

2. Weltevrede, Marlies, et al. “Cytomegalovirus persistence and T-cell immunosenescence in people aged fifty and older: a systematic review.” Experimental gerontology 77 (2016): 87-95.

3. Janssens, Jean-Paul, and Karl-Heinz Krause. “Pneumonia in the very old.” The Lancet infectious diseases 4.2 (2004): 112-124. http://www.pneumonologia.gr/arti…

4. Kaplan, Vladimir, et al. “Hospitalized community-acquired pneumonia in the elderly: age-and sex-related patterns of care and outcome in the United States.” American journal of respiratory and critical care medicine 165.6 (2002): 766-772. https://www.researchgate.net/pro…

5. Karlsson, Elinor K., Dominic P. Kwiatkowski, and Pardis C. Sabeti. “Natural selection and infectious disease in human populations.” Nature Reviews Genetics 15.6 (2014): 379-393. Natural selection and infectious disease in human populations

6. Quach, Hélène, and Lluis Quintana-Murci. “Living in an adaptive world: Genomic dissection of the genus Homo and its immune response.” Journal of Experimental Medicine 214.4 (2017): 877-894. http://jem.rupress.org/content/j…

7. Barua, D., and A. S. Paguio. “ABO blood groups and cholera.” Annals of human biology 4.5 (1977): 489-492.

8. Glass, Roger I., et al. “Predisposition for cholera of individuals with o blood group possible evolutionary significance.” American journal of epidemiology 121.6 (1985): 791-796.

9. Harris, Jason B., and Regina C. LaRocque. “Cholera and ABO Blood Group: Understanding an Ancient Association.” The American Journal of Tropical Medicine and Hygiene 95.2 (2016): 263-264. https://pdfs.semanticscholar.org…

10. Liu, Rong, et al. “Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection.” Cell 86.3 (1996): 367-377. https://www.researchgate.net/pro…

11. Dean, Michael, et al. “Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structual gene.” Science 273.5283 (1996): 1856.


Do people in countries with lots of mosquitos get bitten all the time and always have itchy bites? Do you develop a tolerance to bites?


Mosquitoes don’t bite people indiscriminately. Mosquito biting preference is a product of its host seeking behavior which in turn depends on the odor/VOCs (Volatile organic compound – Wikipedia) it detects in its vicinity (1).

  • For example, a 2014 study found a tight link between the expression and ligand sensitivity of the Olfactory receptor – Wikipedia AaegOr4 by domestic mosquitoes and their preference for human odor (2).
  • Not surprising then that a recent study found deodorants could repel mosquitoes (3). Specifically, the deodorant compound isopropyl tetradecanoate was found to inhibit landings of the malaria mosquito Anopheles coluzzi in a repellent bioassay.

Host Skin Microbiota Profile Influences Attractiveness to Mosquitoes

Human odor/VOC is largely a product of skin-resident Microbiota – Wikipedia and it turns out mosquitoes are attracted to specific volatiles produced by specific bacterial species (see below from 4).

A small study on 48 human volunteers found that the African malaria mosquito Anopheles gambiae sensu stricto found individuals with more abundant but less diverse skin bacterial profiles much more attractive compared to those they found poorly attractive (5).

Genetics of Human Odor & Heritability of Attractiveness to Mosquitoes

Attractiveness to mosquitoes is heritable since a twin study found skin volatiles from identical twins were much more highly correlated for mosquito attractiveness compared to non-identical twins (6).

Studies have for long linked the human odor profile to HLA (Human leukocyte antigen – Wikipedia) (7, 8, 9). A small study on 48 human volunteers found those with the HLA gene Cw*07 were more attractive to the malaria mosquito Anopheles gambiae Giles sensu stricto (10). HLA is integral to immune function which in turn clearly helps select an individual’s microbiota composition, though how this is accomplished is still an intensive area of contemporary cutting-edge research.

While human odor is largely the product of human genetics (HLA) and ecology (skin microbiota), it’s also influenced by diet, grooming habits and health status. Studies such as the deodorant study (3) suggest that innate mosquito preference for a particular individual could at least be somewhat mitigated if not thwarted outright.


1. Takken, Willem, and Niels O. Verhulst. “Host preferences of blood-feeding mosquitoes.” Annual review of entomology 58 (2013): 433-453. http://izt.ciens.ucv.ve/ecologia…

2. McBride, Carolyn S., et al. “Evolution of mosquito preference for humans linked to an odorant receptor.” Nature 515.7526 (2014): 222-227. https://pdfs.semanticscholar.org…

3. Verhulst, Niels O., et al. “Attractiveness of volatiles from different body parts to the malaria mosquito Anopheles coluzzii is affected by deodorant compounds.” Scientific reports 6 (2016). https://www.ncbi.nlm.nih.gov/pmc…

4. Takken, Willem, and Niels Verhulst. “Chemical signaling in mosquito-host interactions: the role of human skin microbiota.” Current Opinion in Insect Science (2017).

5. Verhulst, Niels O., et al. “Composition of human skin microbiota affects attractiveness to malaria mosquitoes.” PloS one 6.12 (2011): e28991. http://journals.plos.org/plosone…

6. Fernández-Grandon, G. Mandela, et al. “Heritability of attractiveness to mosquitoes.” PloS one 10.4 (2015): e0122716. http://journals.plos.org/plosone…

7. Wedekind, Claus, and Sandra Füri. “Body odour preferences in men and women: do they aim for specific MHC combinations or simply heterozygosity?.” Proceedings of the Royal Society of London B: Biological Sciences 264.1387 (1997): 1471-1479. https://www.ncbi.nlm.nih.gov/pmc…

8. Wedekind, Claus, and Dustin Penn. “MHC genes, body odours, and odour preferences.” Nephrology Dialysis Transplantation 15.9 (2000): 1269-1271. https://www.researchgate.net/pro…;

9. Savelev, Sergey U., et al. “Individual variation in 3-methylbutanal: a putative link between human leukocyte antigen and skin microflora.” Journal of chemical ecology 34.9 (2008): 1253-1257. https://www.researchgate.net/pro…

10. Verhulst, Niels O., et al. “Relation between HLA genes, human skin volatiles and attractiveness of humans to malaria mosquitoes.” Infection, genetics and evolution 18 (2013): 87-93. https://www.researchgate.net/pro…


If I recover from mild sinus infections without antibiotics, will my immune system become stronger over time than with them?


Avoiding antibiotics for mild infections may be beneficial long-term. Available data suggest different antibiotics perturb human microbiota differently (1; see below from 2).

  • Some broad-spectrum antibiotics clear out many more organisms than others.
  • Some antibiotics have a more long-term impact than others.

Epidemiological studies suggest antibiotics especially when given in early life could have a long-term impact on immune function, specifically in the form of increased risk for immune disorder-linked diseases such as asthma, other allergies such as eczema, and IBD (Inflammatory bowel disease – Wikipedia) such as Crohn’s disease – Wikipedia (see below from 3).

Antibiotics can clear out large swaths of human body-associated microbiota. This can lead to

All these effects can indirectly damage a person’s immune function (see below from 2).

Indirect since antibiotics especially broad-spectrum eliminate many bacterial species making it patently difficult to directly attribute a particular immune function defect to loss of any one specific microbe. Thus, the story perforce needs to be stitched from two disparate pieces of information, each with inherent limitations and biases,

  • Epidemiological assessments of long-term effects of antibiotic exposure on human populations, and
  • Analysis of specific immune system changes after specific experimental antibiotic administration in mouse models.

Epidemiologically, early life antibiotic Rx is strongly associated with several immune disorder phenomena

Specific immune system changes in response to specific experimental antibiotic administration in mouse models

See below from 20.


1. Cervantes, Jorge. “Use your antibiotics wisely. Consequences to the intestinal microbiome.” FEMS microbiology letters 363.10 (2016): fnw081.

2. Lange, Kathleen, et al. “Effects of antibiotics on gut microbiota.” Digestive Diseases 34.3 (2016): 260-268.

3. Langdon, Amy, Nathan Crook, and Gautam Dantas. “The effects of antibiotics on the microbiome throughout development and alternative approaches for therapeutic modulation.” Genome medicine 8.1 (2016): 39. The effects of antibiotics on the microbiome throughout development and alternative approaches for therapeutic modulation

4. Droste, J. H. J., et al. “Does the use of antibiotics in early childhood increase the risk of asthma and allergic disease?.” Clinical & Experimental Allergy 30.11 (2000): 1548-1553.

5. Kozyrskyj, Anita L., Pierre Ernst, and Allan B. Becker. “Increased risk of childhood asthma from antibiotic use in early life.” CHEST Journal 131.6 (2007): 1753-1759. http://flaviomaticorena.com/padr…

6. Risnes, Kari R., et al. “Antibiotic exposure by 6 months and asthma and allergy at 6 years: findings in a cohort of 1,401 US children.” American journal of epidemiology 173.3 (2011): 310-318. https://www.researchgate.net/pro…

7. Russell, Shannon L., et al. “Early life antibiotic‐driven changes in microbiota enhance susceptibility to allergic asthma.” EMBO reports 13.5 (2012): 440-447. http://embor.embopress.org/conte…

8. Stensballe, Lone Graff, et al. “Use of antibiotics during pregnancy increases the risk of asthma in early childhood.” The Journal of pediatrics 162.4 (2013): 832-838. http://ac.els-cdn.com/S002234761…

9. Mai, X‐M., et al. “Antibiotic use in early life and development of allergic diseases: respiratory infection as the explanation.” Clinical & Experimental Allergy 40.8 (2010): 1230-1237. https://www.researchgate.net/pro…

10. Heintze, Konrad, and Karl-Uwe Petersen. “The case of drug causation of childhood asthma: antibiotics and paracetamol.” European journal of clinical pharmacology 69.6 (2013): 1197-1209. https://www.researchgate.net/pro…

11. Teo, Shu Mei, et al. “The infant nasopharyngeal microbiome impacts severity of lower respiratory infection and risk of asthma development.” Cell host & microbe 17.5 (2015): 704-715. https://www.researchgate.net/pro…

12. Metsälä, Johanna, et al. “Mother’s and offspring’s use of antibiotics and infant allergy to cow’s milk.” Epidemiology 24.2 (2013): 303-309. Mother’s and Offspring’s Use of Antibiotics and Infant Aller… : Epidemiology

13. Stefka, Andrew T., et al. “Commensal bacteria protect against food allergen sensitization.” Proceedings of the National Academy of Sciences 111.36 (2014): 13145-13150.

14. Kummeling, Ischa, et al. “Early life exposure to antibiotics and the subsequent development of eczema, wheeze, and allergic sensitization in the first 2 years of life: the KOALA Birth Cohort Study.” Pediatrics 119.1 (2007): e225-e231. http://citeseerx.ist.psu.edu/vie…

15. Tsakok, T., et al. “Does early life exposure to antibiotics increase the risk of eczema? A systematic review.” British Journal of Dermatology 169.5 (2013): 983-991.

16. Hviid, Anders, Henrik Svanström, and Morten Frisch. “Antibiotic use and inflammatory bowel diseases in childhood.” Gut (2010): gut-2010.

17. Shaw, Souradet Y., James F. Blanchard, and Charles N. Bernstein. “Association between the use of antibiotics in the first year of life and pediatric inflammatory bowel disease.” The American journal of gastroenterology 105.12 (2010): 2687-2692. https://www.researchgate.net/pro…

18. Villarreal, Armando A., et al. “Use of broad-spectrum antibiotics and the development of irritable bowel syndrome.” Wmj 111.1 (2012): 17-20. https://www.wisconsinmedicalsoci…

19. Virta, Lauri, et al. “Association of repeated exposure to antibiotics with the development of pediatric Crohn’s disease—a nationwide, register-based Finnish case-control study.” American journal of epidemiology 175.8 (2012): 775-784. https://www.researchgate.net/pro…

20. Becattini, Simone, Ying Taur, and Eric G. Pamer. “Antibiotic-induced changes in the intestinal microbiota and disease.” Trends in molecular medicine 22.6 (2016): 458-478. http://insanemedicine.com/wp-con…


What are the major tumor associated antigens that clearly differentiate them from normal cells?

To start with, tumor-associated antigens (TAA) don’t clearly differentiate them from normal cells. Rather, they are just expressed a lot more by tumor cells compared to normal cells. That’s why tumor-associated, not tumor-specific. Identifying antigens that only tumor, and not normal, cells express at high levels is difficult and a major part of the problem in figuring out how to devise tumor-specific immunotherapies. Ideally such antigens would also be

  • Crucial for tumor survival, else they’d simply mutate away from expressing them.
  • Immunogenic, else the immune system wouldn’t target them.

Tumor antigens have generally been classified into 3 categories, TSA (Tumor-specific antigen) (Tumor antigens recognized by T lymphocytes – Wikipedia), TAA and Cancer-germline or Cancer Testis Antigens (CTA) (1, 2; see below from 3). MAGEA1 – Wikipedia and NY-ESO-1 – Wikipedia are typical examples of CTA.

NGS (Next Generation Sequencing, DNA sequencing – Wikipedia) shows

  • Mutational landscape of human cancers is far more complex than previously envisaged (4).
  • Even different parts of the same tumor carry different mutations (5) and higher intra-tumor neoantigen heterogeneity may be less sensitive to immune checkpoint blockade (6). Such data suggest tumor-neoantigen-specific T cells are present in patients, that checkpoint inhibitors can lift their brakes to trigger effective tumor targeting, but that higher intra-tumor neoantigen heterogeneity may dilute anti-tumor T cell effectiveness, either by diluting antigen dosage or by reducing effectiveness. After all, if many neoantigens are expressed by a tumor, a given T cell would only effectively target some but not all of them.

Indeed this inherent heterogeneity is the bane of current targeted therapeutics, which aren’t personalized but rather stratified (see a below from 7). At the same time, TSAs being unique to each person, indeed to each tumor, forms the basis of active personalized cancer immunotherapy (see c below from 7).

Inherent tumor heterogeneity presents a conundrum. Clearly, true promise of Cancer immunotherapy – Wikipedia lies in harnessing the immunogenic potential of TSAs. Tumor neoantigens can indeed be targeted by the patient’s own immune system as recent studies have found (8, 9, 10).

However, relevant tumor neoantigens likely vary from patient to patient, relevant here meaning potential for being the target of effective immune response. Situation is far more complicated for T cell antigens since relevant ones aren’t simply those neoantigens that the tumor expresses but rather those that can make it through the stringent bottleneck of Antigen processing – Wikipedia and presentation to get presented to tumor-specific T cells by MHC class I – Wikipedia or MHC class II – Wikipedia. The patient’s HLA (Human leukocyte antigen – Wikipedia) haplotype will thus also be a crucial parameter.

Such considerations imply personalized approaches rather than ‘off-the-shelf’ products will likely yield the most effective cancer immunotherapy. A conundrum because individualized Rx approaches present a challenge for regulators (7). How to mitigate risk? How to assess safety, toxicity? All the steps comprising the well trod path applied to ‘off-the-shelf’ products aren’t feasible. Figuring out how to mitigate risk and keep costs down enough to make such treatments practicable for many and not just the purview of the super-rich are the major stumbling blocks for future TSA-based personalized cancer immunotherapy.


1. Heemskerk, Bianca, Pia Kvistborg, and Ton NM Schumacher. “The cancer antigenome.” The EMBO journal 32.2 (2013): 194-203. http://emboj.embopress.org/conte…

2. Coulie, Pierre G., et al. “Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy.” Nature Reviews Cancer 14.2 (2014): 135-146. https://www.researchgate.net/pro…

3. Yarchoan, Mark, et al. “Targeting neoantigens to augment antitumour immunity.” Nature Reviews Cancer (2017).

4. Sjöblom, Tobias, et al. “The consensus coding sequences of human breast and colorectal cancers.” science 314.5797 (2006): 268-274. https://www.researchgate.net/pro…

5. Gerlinger, Marco, et al. “Intratumor heterogeneity and branched evolution revealed by multiregion sequencing.” N Engl j Med 2012.366 (2012): 883-892. http://www.nejm.org/doi/pdf/10.1…

6. McGranahan, Nicholas, et al. “Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade.” Science 351.6280 (2016): 1463-1469. https://www.ncbi.nlm.nih.gov/pmc…

7. Britten, Cedrik M., et al. “The regulatory landscape for actively personalized cancer immunotherapies.” Nature biotechnology 31.10 (2013): 880-882. The regulatory landscape for actively personalized cancer immunotherapies

8. Brown, Scott D., et al. “Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival.” Genome research 24.5 (2014): 743-750. Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival

9. Tran, Eric, et al. “Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer.” Science 344.6184 (2014): 641-645.

10. Linnemann, Carsten, et al. “High-throughput epitope discovery reveals frequent recognition of neo-antigens by CD4+ T cells in human melanoma.” Nature medicine 21.1 (2015): 81-85.