Why doesn’t the CDC or WHO offer more seasonal flu candidate vaccine viruses (CVVs)? Given that it takes a long time to grow the vaccine to make a flu shot, why not make several versions and pick the most effective at the time of flu shot injections?

Why doesn’t the CDC or WHO offer more seasonal flu candidate vaccine viruses (CVVs)? Given that it takes a long time to grow the vaccine to make a flu shot, why not make several versions and pick the most effective at the time of flu shot injections?

This answer briefly covers

  • The global seasonal flu vaccine production process: how it starts, the key players, etc.
  • How egg-based flu vaccine production is its major bottleneck.

The clock for the Northern Hemisphere annual seasonal flu vaccine starts in February with the WHO, which coordinates the Global Influenza Surveillance and Response System (GISRS), a group of 143 WHO-designated National Influenza Centers (NICs) in 113 WHO Member States plus 6 WHO Influenza Collaborating Centers and several Regulatory and Reference labs.

  • These NICs isolate the viruses presently circulating in their countries/regions and submit them to CCs which conduct detailed antigenic analysis to determine the influenza A and B subtypes.
  • The WHO then makes a worldwide recommendation of the influenza A and B strains to be used for the upcoming season’s vaccine, which needs to be adapted to the local epidemiological situation in each country/region.
  • For example, the FDA makes the local decision in the US by selecting the strains to include for that year in the US.

See sequentially below text from 1, emphasis mine, and table from 2.

‘These WHO recommendations provide a guide to national public health and regulatory authorities and vaccine manufacturers for the development and production of influenza vaccines for the next influenza season. In contrast to many other vaccines, the viruses in influenza vaccines have to be evaluated and updated regularly because circulating influenza viruses continuously evolve. Recommendations are made in February/March for the following influenza season in the northern hemisphere and in September for the following influenza season in the southern hemisphere because approximately 6-8 months are needed to produce and approve vaccines. WHO has formulated guidance for countries in tropical and sub-tropical regions to assist them in choosing which vaccine composition (February/March or September) is most appropriate (Seasonal influenza vaccine in tropics and subtropics).’Using eggs to grow seasonal flu vaccine is the major bottleneck in its production (see below from 3).

Using eggs to grow seasonal flu vaccine is the major bottleneck in its production (see below from 3).

Egg-based flu vaccines have all sorts of drawbacks

  • Take at least 6 months, a length of time that ends up creating other problems.
  • Logistically, vaccine design can’t be tweaked on a dime midway and yet sufficient amounts made in time for flu season once the annual process starts.
  • Egg supply can be threatened or inadequate during avian flu epidemics.
  • Currently the decision for which flu strains should be included is made ~9 months before the start of the next flu season to give enough time to produce and distribute the vaccine. This decision is based on an early snapshot which gives a longer window of opportunity for new antigenic variants to emerge among the strains circulating in the human population, the so-called mismatch issue caused by flu virus’ prodigious ability to engage in Antigenic drift – Wikipedia.
  • The longer it takes to grow the flu strains inside chicken eggs, the greater the opportunity for flu virus variants to emerge. Often this process-associated limitation is the reason for reduced flu vaccine efficacy.
    • Egg-adapted flu strains can often be antigenically different and thus may end up driving immune responses to such irrelevant antigens rather than to those that are expressed by the circulating flu strains that are infecting humans during a given flu season (4).
    • While such mutation propensity was observed all the way back in 1980 (5), frequent occurrences of low flu vaccine effectiveness in recent years has now made it a front and center issue.
    • Egg-adaption induced mutations in flu strains seem to be especially a problem with H3N2 flu strains (6),which seem prevalent in the 2017-2018 flu season.

These types of process-associated artifacts are frequently the reason for low flu vaccine efficacy. So what to do about it? Other approaches to produce seasonal flu vaccine include cell-based, recombinant protein-based or plant based (see below from 7).

Problem is such approaches have been discussed and explored for years but none has yet broken through into the mainstream. Reasons for delay include the protracted length and expense for each approach to pass muster, which requires the expensive proposition of undertaking a series of clinical trials that pass the benchmarks for safety and efficacy. While these approaches are being put to the test in this fashion, none is yet close to the finish line.

Another is the holy grail of universal flu vaccines (8, 9). Hold up there is

  • Incomplete knowledge of what an effective immune response to flu entails.
  • Which specific immune response elements are both necessary and sufficient.
  • Different studies spotlight different features while what constitutes flu Correlates of immunity/correlates of protection – Wikipedia is still a matter of debate.

Thus, notwithstanding its many drawbacks including variable efficacy, given its proven track record of safety, and tried and tested production process, the 70 year old egg-based seasonal flu vaccine unfortunately currently remains a mainstay.


1. http://www.who.int/influenza/vac…

2. Brooks, W. Abdullah, and Mark C. Steinhoff. “Epidemiology of influenza in tropical and subtropical low-income regions.” Influenza vaccines for the future. Springer, Basel, 2011. 55-75. https://the-eye.eu/public/Books/…

3. http://www.multivu.com/players/E…

4. Raymond, Donald D., et al. “Influenza immunization elicits antibodies specific for an egg-adapted vaccine strain.” Nature medicine 22.12 (2016): 1465. https://crystal.harvard.edu/PDFs…

5. Brand, Colin, and Peter Palese. “Sequential passage of influenza virus in embryonated eggs or tissue culture: emergence of mutants.” Virology 107.2 (1980): 424-433.

6. Skowronski, Danuta M., et al. “Low 2012–13 influenza vaccine effectiveness associated with mutation in the egg-adapted H3N2 vaccine strain not antigenic drift in circulating viruses.” PloS one 9.3 (2014): e92153.

7. Effectiveness of the seasonal flu vaccine and new production methods

8. Paules, Catharine I., et al. “The Pathway to a Universal Influenza Vaccine.” Immunity 47.4 (2017): 599-603.

9. Paules, Catharine I., et al. “Chasing Seasonal Influenza—The Need for a Universal Influenza Vaccine.” New England Journal of Medicine 378.1 (2018): 7-9. http://www.nejm.org/doi/pdf/10.1…



Is it appropriate to make citations to papers published as preprint when writing a research or review article?


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Is it appropriate to make citations to papers published as preprint when writing a research or review article?

Preprints have long been a staple in disciplines such as physics, mathematics, economics, philosophy, political science while they’re a relative novelty in biology (and biomedical science), the focus of this answer. Preprints are scientific manuscripts directly posted to preprint servers, side-stepping a key pillar of the modern scientific process, Peer review – Wikipedia. Note that such side-stepping is for the most part, at least so far, only temporary since analyses suggest peer-reviewed versions of biology preprints eventually end up getting published in mainstream scientific journals anyway.

Nevertheless, courtesy their novelty, preprints remain an unfamiliar entity to many in biology. Biology preprints thus occupy a rapidly changing space in scientific publishing, with the entry of several new players as well as major funders and investors injecting substantial investments in recent years. Journal and grant funder policies with respect to preprints are currently fluid so researchers should actively monitor policy updates.

This answer considers

  • Whether scientific publishers accept biology preprints as citations (references) in research articles submitted for peer-review.
  • Whether grant funders allow applications to cite biology preprints in their submissions.

Do scientific publishers accept biology preprints as citations (references) in research articles submitted for peer-review with them? Some do, others may not. Check individual journal/publisher policy.

Manuscript submission policies can be vastly different from one scientific publisher to another. For example, NPG (Nature Publishing Group – Wikipedia) states (1, see below from emphasis mine),

‘Only articles that have been published or accepted by a named publication, or that have been uploaded to a recognized preprint server (for example, arXiv, bioRxiv), should be in the reference list; papers in preparation should be mentioned in the text with a list of authors (or initials if any of the authors are co-authors of the present contribution).

Published conference abstracts, numbered patents, preprints on recognized servers (preprints of accepted papers in the reference list should be submitted with the manuscript) and research datasets that have been assigned a digital object identifier may be included in reference lists, but text, grant details and acknowledgements may not.’

However, other publishers may not allow such citations so authors should check the written manuscript submission policies of the individual journal/publisher.

Next, let’s examine the citation index of a preprint first posted to the preprint server, bioRxiv, on November 25, 2015 (2).

Google Scholar shows one version of this preprint being cited 40 times so far (as of January 31, 2018) including by papers published in the peer-reviewed journals, Nature and Lancet Infectious Diseases (see below).

In any case, preprints such as this one which happen to be cited rather robustly offer another way to find out which journals allow preprints to be cited. Simply look them up on bibliographic databases such as Google Scholar (free), Scopus or Web of Science (subscription only) for journal articles that cited them.

Do grant funders allow applications to cite biology preprints in their submissions? Yes, many do.

A recent review in Science magazine calls itself a survival guide for preprints and is well worth the read (see below from 3),

‘Major research funders have also moved to legitimize preprints. The U.K. Medical Research Council and the Wellcome Trust in London, as well as NIH and the Howard Hughes Medical Institute in Chevy Chase, Maryland, now encourage grantees to cite preprints—not just peer-reviewed papers—in grant proposals. CZI [Chan-Zuckerberg Initiative] has even made posting a preprint (at the same time as the paper is submitted to a journal) a requirement for its grantees…Because preprints can be cited, they can help young scientists quickly build a scholarly track record.’

Other articles in the peer-reviewed scientific literature echo the point that preprints can be cited in grants and fellowship applications (see below from 4),

‘Many journals will now consider an article that has appeared on a preprint server, and grant-awarding bodies on both sides of the Atlantic allow preprints to be cited in grant and fellowship applications‹some, such as the Chan Zuckerberg Initiative, insist that their investigators deposit their papers as preprints.’

Another peer-reviewed analysis of biology preprints notes similarly (see below from 5),

‘A growing number of scientific societies and journals, including ASM [American Society for Microbiology], view preprints as citable and as having a legitimate claim to primacy (1, 20–22); however, it remains to be determined whether the journals will stand by these policies…several funding agencies, including the NIH, Wellcome Trust, and UK Medical Research Council, encourage fellowship applicants to include preprints in their materials.’


1. Formatting guide,

2. de Melo Freire, Caio Cesar, et al. “Spread of the pandemic Zika virus lineage is associated with NS1 codon usage adaptation in humans.” BioRxiv (2015): 032839. https://www.biorxiv.org/content/…

3. Kaiser, Jocelyn. “The preprint dilemma.” (2017): 1344-1349. The preprint dilemma

4. Cobb, Matthew. “The prehistory of biology preprints: a forgotten experiment from the 1960s.” PLoS biology 15.11 (2017): e2003995. http://journals.plos.org/plosbio…

5. Schloss, Patrick D. “Preprinting microbiology.” mBio 8.3 (2017): e00438-17. Preprinting Microbiology


Can infectious diseases like the flu be spread thru the mail and packages?

Can infectious diseases like the flu be spread thru the mail and packages?

In order to spread from surfaces, infectious agents such as flu viruses have to first survive on them. Lab simulations suggest flu viruses survive less well on porous surfaces such as cloth and paper compared to non-porous surfaces such as stainless steel and plastic. We could surmise from such studies that paper is not as effective in facilitating the spread of flu compared to other surfaces.

Different infectious agents spread through vastly different means, air, fecal-oral, bodily fluids, direct touch, from surfaces and so on. Unlike many other infectious agents, it’s much more difficult to quickly identify and isolate flu-infected patients given the virus’ short incubation period, capacity to spread through many routes and its ability to generate new rapidly spreading strains. These are some of the crucial factors that facilitate its rapid spread.

For flu to spread thru the mail and packages it needs to stay viable on such porous surfaces for long periods of time. More studies have examined flu survival on surfaces such as steel, plastic, cloths, fewer on paper, the focus of this answer.

  • A 1982 study examined ability of flu virus to retain infectiousness after being applied (100 to 1000 plaque-forming units) on stainless steel surfaces, hard plastic, paper and cotton (1). It found both influenza A and B strains could survive for 24 to 48 hours on steel or plastic surfaces and get transferred onto hands even 24 hours later. OTOH, flu survived 8 to 12 hours on paper or cotton while it could be successfully transferred from such surfaces for only ~15 minutes.
  • A 2008 study found both H1N1 and H3N2 strains of seasonal flu (10000 to 1 million plaque-forming units) survived on Swiss banknotes for up to 3 days at higher doses (2). This survival increased to ~17 days when they used children’s snot to apply the virus.
  • A 2011 study found several flu strains (1 million plaque-forming units) applied to a variety of surfaces including cloth and soft toy (not paper) survived ~9 hours (3). Cloth and soft toys also being porous makes these results somewhat relevant for paper.

Results of such studies come with a number of important caveats since lab simulations leave a lot to be desired when compared to real-life settings.

  • In real life a given surface is likely to be subjected to repeated re-inoculations by an infected person.
  • Flu virus is deposited as part of human snot and a 1944 study found it survived better in human mucus (4).
  • Temperature and humidity greatly influence flu survival and viability while salinity and pH also affect its persistence in liquids (5). However, flu survival studies on surfaces haven’t considered the effect of these additional environmental factors.
  • Different studies used different doses, different flu strains, different types of surfaces. Results from any one study thus have limited scope for generalization.
  • In real life, infected people can spread flu both when they exhale and when they cough. Virus expelled during cough emerges from deeper within the lung while virus expelled during exhalation is more typically sourced from the upper respiratory tract. Open question remains whether virus expelled from these two different acts (and locations) within an infected person are different in dose and virulence (capacity to infect).


1. Bean, B., et al. “Survival of influenza viruses on environmental surfaces.” Journal of Infectious Diseases 146.1 (1982): 47-51.

2. Thomas, Yves, et al. “Survival of influenza virus on banknotes.” Applied and environmental microbiology 74.10 (2008): 3002-3007. Survival of Influenza Virus on Banknotes

3. Greatorex, Jane S., et al. “Survival of influenza A (H1N1) on materials found in households: implications for infection control.” PloS one 6.11 (2011): e27932. http://journals.plos.org/plosone…

4. Parker, Ernestine R., Wolcott B. Dunham, and Ward J. MACNEAL. “Resistance of the Melbourne strain of influenza virus to desiccation.” Journal of Laboratory and Clinical Medicine 29.1 (1944): 37-2.

5. Irwin, Christa K., et al. “Using the systematic review methodology to evaluate factors that influence the persistence of influenza virus in environmental matrices.” Applied and environmental microbiology 77.3 (2011): 1049-1060. Using the Systematic Review Methodology To Evaluate Factors That Influence the Persistence of Influenza Virus in Environmental Matrices


Given blood viral levels that are below detection, what is the transmission risk (probability) for Hepatitis B virus?

Given blood viral levels that are below detection, what is the transmission risk (probability) for Hepatitis B risk?

Someone infected with Hepatitis B virus (HBV) should consider ‘given blood viral levels that are below detection‘ as not sufficiently informative.

Blood viral DNA levels are only one of several serological markers that indicate HBV infection. Others include levels of HBsAg (HBV surface antigen), HBeAg (HBV e antigen) as well as presence and amounts of antibodies against these and other HBV antigens. Each of these markers conveys information about the underlying stage of infection and corresponding immune response against it, which influence transmission risk (1; also see table below from 2).

  • Profiles of acute and chronic HBV infection are different in key aspects of virus and anti-viral immune response.
  • HBV DNA represents a measure of viral load and indicates HBV replication.
  • Currently, levels of HBeAg and antibodies against it largely determine chronicity which could last for years if HBeAg persists.
  • Positivity for HBeAg suggests high level of HBV replication as well as high infectivity.
  • HBV infection is also considered chronic if HBsAg persists for >6 months.
  • Positivity for HBsAg indicates infectivity.
  • Anti-HBeAg antibodies suggest effective immune response meaning reduction in HBV replication and improvement in liver function readouts such as ALT (alanine aminotransferase) levels. However, this phase can also revert.
  • Occult infection may be suspected when HBsAg is undetectable in the presence of detectable HBV DNA.

Further, ‘given blood viral levels that are below detection‘ should be seen not as standalone but as a snapshot subject to change depending on factors not all of which are within an individual’s control, factors such as age, acquiring other infections such as HCV, HIV, unanticipated life stresses that can diminish immune health as well as sexual orientation which alters risk factors.

  • HBV can reactivate in inactive carriers after immunosuppression or cancer chemotherapy (3).
  • Among HBeAg seroconverters, i.e., those with antibodies against HBeAg, the factors associated with HBV reactivation include
    • HBV genotype, with some genotypes more likely to reactivate compared to others, Genotype C > B (4), Genotype D > A (5).
    • Older than 30 years at time of HBeAg seroconversion (4, 5, 6, 7, 8).
  • Risk of horizontal and vertical (mother-to-fetus) HBV transmission are also different.

In short, prognostication of transmission risk from apparently chronic HBV infection is complicated to say the least. However, the latest recommendations from the US Advisory Committee on Immunization Practices – Wikipedia outline (1, emphasis mine),

‘…Persons who recover from natural HBV infection are typically positive for both anti-HBs [antibody against Hepatitis B surface antigen] and anti-HBc [antibody against Hepatitis B core antigen] , whereas persons who respond to HepB vaccine are positive only for anti-HBs. Approximately 0.5%–2% of persons with chronic infection spontaneously clear HBsAg yearly; anti-HBs will develop in the majority of these persons (8).

In certain persons, anti-HBc is the only serologic marker detected. Isolated anti-HBc-positivity can be detected following HBV infection in persons who have recovered but whose anti-HBs levels have waned; in populations with a high prevalence of HBV infection, isolated anti-HBc likely indicates previous infection with loss of anti-HBs. Some chronically infected persons with isolated anti-HBc-positivity have circulating HBsAg that is not detectable by a laboratory assay. HBV DNA has been detected in <10% of persons with isolated anti-HBc (70,71), although the presence of detectable HBV DNA might fluctuate (72). These persons are unlikely to transmit infection except under circumstances in which they are the source of a large exposure, such as a blood transfusion (8,73). Persons who are HBsAg-negative and anti-HBc-positive can experience reactivation of infection during chemotherapy or immunosuppressive therapy, with reappearance of HBsAg (49). ‘

The freely available WHO guidelines on Hepatitis B and C testing (9) are also a very useful reference guide. See pages 19 to 24 for Hepatitis B.


1. Schillie, Sarah. “Prevention of Hepatitis B Virus Infection in the United States: Recommendations of the Advisory Committee on Immunization Practices.” MMWR. Recommendations and Reports 67 (2018). https://www.cdc.gov/mmwr/volumes…

2. https://cdn.hiv.uw.edu/pdf/co-oc…

3. Perrillo, Robert P. “Acute flares in chronic hepatitis B: the natural and unnatural history of an immunologically mediated liver disease.” Gastroenterology 120.4 (2001): 1009-1022. http://www.gastrojournal.org/art…

4. Chu, Chia–Ming, and Yun–Fan Liaw. “Predictive factors for reactivation of hepatitis B following hepatitis B e antigen seroconversion in chronic hepatitis B.” Gastroenterology 133.5 (2007): 1458-1465. http://www.gastrojournal.org/art…

5. Sánchez-Tapias, José M., et al. “Influence of hepatitis B virus genotype on the long-term outcome of chronic hepatitis B in western patients.” Gastroenterology 123.6 (2002): 1848-1856. http://www.gastrojournal.org/art…

6. Chu, Chia‐Ming, and Yun‐Fan Liaw. “HBsAg seroclearance in asymptomatic carriers of high endemic areas: Appreciably high rates during a long‐term follow‐up.” Hepatology 45.5 (2007): 1187-1192. http://onlinelibrary.wiley.com/d…

7. Chu, Chia-Ming, and Yun-Fan Liaw. “Spontaneous relapse of hepatitis in inactive HBsAg carriers.” Hepatology international 1.2 (2007): 311-315. https://www.ncbi.nlm.nih.gov/pmc…

8. Chen, Yi‐Cheng, Chia‐Ming Chu, and Yun‐Fan Liaw. “Age‐specific prognosis following spontaneous hepatitis B e antigen seroconversion in chronic hepatitis B.” Hepatology 51.2 (2010): 435-444. http://onlinelibrary.wiley.com/d…

9. World Health Organization. “WHO guidelines on hepatitis B and C testing.” (2017). http://apps.who.int/iris/bitstre…


Has enough research been done on Ebola?

Has enough research been made on Ebola? What do you people think?

If we liken Ebola research to a race, it wouldn’t be a stretch to say that it’s barely off the starting block (1, 2, 3, 4, 5).

  • Easy to diagnose Ebola? No.
  • Easy to treat Ebola? No.
  • Safe and effective vaccine against Ebola? No.

Notwithstanding that bleak background, the last Ebola outbreak from March 2014 until June 2016 in West Africa certainly accelerated research on it. For example, it stoked rapid development of commercial kits for Ebola diagnosis, several of which have now made it onto the WHO’s roster of approved test kits (6, 7).

While most of these diagnostic methods require sophisticated infrastructure, equipment and training, and thus can only be performed in reference laboratories, not at the patient’s bedside, a handful are rapid ones that can be done cheaply on site and most importantly, are quite sensitive as well as specific (8).

Situation is however a lot worse with respect to therapy with no single Ebola treatment as yet approved for humans, a major obstacle since its mortality rate remains quite high, ranging from 79% in the past to ~40% in the 2014-2016 West African outbreak (9).

Even something as seemingly simple as optimizing the standard of care may go a long way in reducing Ebola mortality rates. Such standard of care boils down to simple interventions as oral rehydration, electrolyte replacement, anti-symptomatics such as for fever, vomiting and diarrhea, adequate nutrition, timely treatment of accompanying infections such as malaria or bacterial infections (10). Point is even such a simple first step disease management approach didn’t exist for Ebola until this latest major outbreak.

Ebola outbreaks have been relatively rare and usually occur in remote regions, factors that make it very difficult to gather clinical efficacy data on experimental therapies since it’s next to impossible to conduct clinical trials in an outbreak setting (11). The FDA’s Animal Rule, Animal efficacy rule – Wikipedia, is meant to expedite therapies by relying mainly on animal model data, unlike the process by which therapies are usually approved for human use. Even so, getting approved therapies for a disease that shows up as outbreaks in remote regions is challenging.

Reliable point of care diagnostics and at least one or two safe, effective and relatively cheap therapies, one could say Ebola research reached commendable milestones when these become everyday realities. While the first goal appears within reach, that’s not the case with the second one.


1. http://www.who.int/ebola/22-5-17…

2. http://apps.who.int/iris/bitstre…

3. http://www.who.int/medicines/ebo…

4. http://www.who.int/immunization/…

5. http://www.who.int/immunization/…

6. Diagnostics

7. Ebola EUAL Status after PHEIC Termination

8. Mérens, A., C. Bigaillon, and D. Delaune. “Ebola virus disease: Biological and diagnostic evolution from 2014 to 2017.” Medecine et maladies infectieuses (2017).

9. 2014-2016 Ebola Outbreak in West Africa

10. Duraffour, Sophie, Denis Malvy, and Daouda Sissoko. “How to treat Ebola virus infections? A lesson from the field.” Current opinion in virology 24 (2017): 9-15. https://www.sciencedirect.com/sc…

11. Rojek, Amanda M., et al. “Regulatory and operational complexities of conducting a clinical treatment trial during an Ebola Virus Disease epidemic.” Clinical Infectious Diseases (2017). Regulatory and Operational Complexities of Conducting a Clinical Treatment Trial During an Ebola Virus Disease Epidemic | Clinical Infectious Diseases | Oxford Academic


A baby usually inherits its mother’s immunity. Does a lady who emigrated from West Africa to the US still have a higher level of immunity to malaria and some other tropical illnesses? And has she been able to pass that level of immunity to her baby?


A baby usually inherits its mother’s immunity. Does a lady who emigrated from West Africa to the US still have a higher level of immunity to malaria and some other tropical illnesses? And has she been able to pass that level of immunity to her baby?

These questions can be re-stated as

  • How long is a migrant protected after moving away from a malaria*-endemic region such as West Africa? A few years.
  • Do mothers pass protective anti-malaria immunity to babies? How long does such protection last? Yes, ~6 to 9 months.

* Features pertinent to anti-malaria immunity are broadly applicable to other tropical illnesses.

How long is an emigrant protected after moving away from a malaria-endemic region such as West Africa?

To understand how long naturally acquired immunity protects against malaria requires longitudinal migrant Cohort study – Wikipedia that follow groups of 1st generation migrants who have moved away from malaria-endemic regions and periodically return to visit friends and relatives. Such studies should then assess

  • How many caught malaria from their return trip(s).
  • How many got the severe form.
  • The relationship between length of time away and risk of clinical malaria, especially severe malaria.

Though few malaria studies have examined such issues in depth, a handful permit some general inferences.

  • More the frequency and number of prior exposures to malaria, stronger the likelihood a person has developed robust immunity against it. This means more a migrant got exposed to malaria before they left, greater their likelihood of retaining protective immunity for longer after they move away.
    • Studies from Papua (1), Kenya, Gambia (2), and Kenya again (3) suggest as much.
  • Severe Plasmodium falciparum malaria and even deaths are less frequent among sub-Saharan migrants compared to other travelers to malaria-endemic regions.
    • Less severe malaria could be lower parasite density, less frequent presentation of clinically severe malaria, and/or faster clearance of both parasites and fever.
    • Studies from Europe (4), France (5, 6, 7, 8), Italy (9, 10), Poland (11) and UK (12) suggest as much.
  • However, longer a migrant stays away from malaria exposure, more their risk of severe malaria resembles that of a non-exposed traveler. This is because protection by naturally acquired immunity wanes over time. A small study from Sweden found immigrants who had lived in Sweden for >15 years had similar risk of severe malaria as those not previously exposed to it (13). More such studies would help generalize how long protective natural anti-malaria immunity might last.

Do mothers pass protective anti-malaria immunity to babies? How long does such protection last?

Barring risk factors such as malnutrition and exposure to malaria in utero, babies and infants <6 months of age in malaria-endemic regions rarely show clinical signs of malaria (fever, high levels of parasite in blood).

  • This is understood as mother having passed protective IgG antibodies against malaria to baby (14).
  • A handful of studies in the 1960s found dramatic improvement in malaria symptoms in hospitalized children given serum from healthy adults with naturally acquired immunity to malaria (15, 16). However, details of this process remain sketchy and poorly understood even today.
  • Amount of protective anti-malaria antibodies passed from mother to baby matters (17, 18).
  • Thus we’re back to where we started, more exposure of a migrant mother to malaria before they leave, more robust their naturally acquired immunity and higher the levels of protective antibodies they transfer to their baby.
  • Protective maternal antibody levels typically wane by 6 to 9 months of age, meaning protection to baby is time-limited.


1. Doolan, Denise L., Carlota Dobaño, and J. Kevin Baird. “Acquired immunity to malaria.” Clinical microbiology reviews 22.1 (2009): 13-36. Acquired Immunity to Malaria

2. Gupta, Sunetra, et al. “Immunity to non-cerebral severe malaria is acquired after one or two infections.” Nature medicine 5.3 (1999): 340. https://www.researchgate.net/pro…

3. Kurtis, Jonathan D., et al. “Human resistance to Plasmodium falciparum increases during puberty and is predicted by dehydroepiandrosterone sulfate levels.” Infection and immunity 69.1 (2001): 123-128. http://iai.asm.org/content/69/1/…

4. Jelinek, T., et al. “Imported Falciparum malaria in Europe: sentinel surveillance data from the European network on surveillance of imported infectious diseases.” Clinical Infectious Diseases 34.5 (2002): 572-576. https://www.researchgate.net/pro…

5. Bouchaud, Olivier, et al. “Do African immigrants living in France have long-term malarial immunity?.” The American journal of tropical medicine and hygiene 72.1 (2005): 21-25. https://www.researchgate.net/pro…

6. Legros, Fabrice. “Risk factors for imported fatal Plasmodium falciparum malaria, France, 1996–2003.” (2007).

7. Pistone, T., et al. “Epidemiology of imported malaria give support to the hypothesis of ‘long-term’semi-immunity to malaria in sub-Saharan African migrants living in France.” Travel medicine and infectious disease 12.1 (2014): 48-53. http://www.travelmedicinejournal…

8. Argy, Nicolas, et al. “Influence of host factors and parasite biomass on the severity of imported Plasmodium falciparum malaria.” PloS one 12.4 (2017): e0175328. http://journals.plos.org/plosone…

9. Castelli, F., et al. “Malaria in migrants.” Parassitologia 41.1-3 (1999): 261-265.

10. Mascarello, Marta, et al. “Imported malaria in immigrants to Italy: a changing pattern observed in north eastern Italy.” Journal of travel medicine 16.5 (2009): 317-321. http://onlinelibrary.wiley.com/d…

11. Stępień, Małgorzata, and Magdalena Rosińska. “Imported malaria in Poland 2003 to 2011: implications of different travel patterns.” Journal of travel medicine 21.3 (2014): 189-194. http://onlinelibrary.wiley.com/d…

12. Phillips, Anastasia, et al. “Risk factors for severe disease in adults with falciparum malaria.” Clinical Infectious Diseases 48.7 (2009): 871-878. https://www.researchgate.net/pro…

13. Färnert, A., et al. “Duration of residency in a non-endemic area and risk of severe malaria in African immigrants.” Clinical Microbiology and Infection 21.5 (2015): 494-501. http://www.clinicalmicrobiologya…

14. Dobbs, Katherine R., and Arlene E. Dent. “Plasmodium malaria and antimalarial antibodies in the first year of life.” Parasitology 143.2 (2016): 129-138. https://www.cambridge.org/core/s…

15. Cohen, S., I. A. McGregor, and S. Carrington. “Gamma-globulin and acquired immunity to human malaria.” Nature 192 (1961): 733-7.

16. McGregor, I. A. “The passive transfer of human malarial immunity.” The American journal of tropical medicine and hygiene 13.1_Part_2 (1964): 237-239.

17. Murungi, Linda M., et al. “A threshold concentration of anti-merozoite antibodies is required for protection from clinical episodes of malaria.” Vaccine 31.37 (2013): 3936-3942. https://pdfs.semanticscholar.org…

18. Murungi, Linda M., et al. “Cord blood IgG and the risk of severe Plasmodium falciparum malaria in the first year of life.” International journal for parasitology 47.2-3 (2017): 153-162. https://pdfs.semanticscholar.org…



How can you determine if an individual has previously been infected with Dengue?


How can you determine if an individual has been previously been infected with Dengue?

As with any other infectious agent, Dengue virus – Wikipedia infection could be primary or a repeat such as secondary and so on. Dengue’s a blood-borne infection and blood is easily accessible so no surprise it’s the primary source material used for its diagnosis. Typically, lab diagnosis of Dengue entails measuring one or more of the following in serum,

  • Dengue virus titer.
  • Levels of one of its envelope protein called NS1 (non-structural protein 1), NS1 antigen test – Wikipedia.
  • Anti-Dengue IgM antibodies (indicative of primary [naive] immune response).
  • Anti-Dengue IgG antibodies (indicative of secondary [activated &/ memory] immune response).

Obviously, Immunological memory – Wikipedia predicates that memory immune responses induced by prior Dengue infection would kick in rapidly following a secondary infection and would influence its course. Thus main differences observed between primary and secondary Dengue infections are (also see below from 1).

  • Virus titers and NS1 envelope protein levels persist at higher levels for longer in primary infection (top panel below) and decline much more rapidly in secondary infection (bottom panel below).
  • Anti-Dengue IgG appears late, by ~ day 7 in primary (top panel below) and early, by ~ day 2, reaching higher levels in secondary infections (bottom panel below).

Also note of course, real life is far messier in that Dengue antigens overlap a great deal with those of other Flavivirus – Wikipedia such as Japanese encephalitis – Wikipedia, Yellow fever – Wikipedia and Zika virus – Wikipedia, which makes its diagnosis challenging, especially in regions where these viruses are endemic (Endemism – Wikipedia).

WHO Dengue guidelines are also a most useful resource for all things Dengue and available for free to boot: World Health Organization, et al. Dengue: guidelines for diagnosis, treatment, prevention and control. World Health Organization, 2009. http://www.who.int/tdr/publicati…


1. Muller, David A., Alexandra CI Depelsenaire, and Paul R. Young. “Clinical and Laboratory Diagnosis of Dengue Virus Infection.” The Journal of infectious diseases 215.suppl_2 (2017): S89-S95. Clinical and Laboratory Diagnosis of Dengue Virus Infection | The Journal of Infectious Diseases | Oxford Academic


Is there a cure for diabetes?

Is there a cure for diabetes?

So far concerted lifestyle changes such as diet and exercise are known to reverse diabetes while there are no known/approved medical cures.

In diabetes, either the pancreas makes insufficient levels of insulin so cells absorb glucose poorly or cells themselves become insulin resistant and thus unable to absorb glucose despite adequate insulin levels. Both types of change increase blood sugar levels above normal. Parsed this way, type I and type II diabetes overlap some but also differ.

In type I diabetes, insufficient levels of insulin result from the immune system itself attacking the pancreatic beta cells. OTOH, while beta cell dysfunction varies widely between type II diabetes patients, insulin resistance is a major part of the disease. Restoring the beta cells of the pancreas to health is the treatment approach these two diseases share to some degree.

Clinical attempts to treat type I diabetes focus on either replacing the damaged pancreas with a healthy one through islet cell or pancreas transplant or targeting the Adaptive immune system – Wikipedia in an effort to stave further damage to the pancreas. However, these efforts have several shortcomings.

  • Donors are in very short supply.
  • A systematic review finds transplant results themselves tend to vary a lot (1).
  • Treatments to target the immune system to halt its attack of pancreas remain blunt and non-specific.

Meantime, tremendous interest in using different types of Stem cell – Wikipedia, mesenchymal, bone-marrow or from umbilical cord blood, to try to regenerate the pancreas motivated many clinical trials for both type I and type II diabetes in recent years with mixed results. A 2016 Meta-analysis – Wikipedia concluded (see below from 3).

‘On the basis of our study, we conclude the following: (1) remission of DM [Diabetes mellitus] is possible following stem cell therapy; (2) stem cell transplantation can be a safe and effective approach for therapy of DM; (3) available data from these clinical trials indicate that the most promising therapeutic outcome was shown in mobilized marrow CD34+ HSCs; [hematopoietic stem cells] (4) patients with previously diagnosed diabetic ketoacidosis are not good candidates for the applied approaches stem cell therapy; (5) stem cell therapy at early stages after DM diagnosis is more effective than intervention at later stages; and (6) well-designed large scale randomized studies considering the stem cell type, cell number, and infusion method in DM patients are urgently needed.’

Recent global increase in diabetes, especially type II diabetes, is a product of the global obesity epidemic and attendant increase in Metabolic syndrome – Wikipedia. In turn this has fueled an increase in surgical intervention in the form of Bariatric surgery – Wikipedia. Diabetes reversal often follows sustained weight loss and indeed a 2014 Cochrane review of such surgeries found diabetes improvement in 5 randomized clinical trials (4). However, depending on the country and insurance plans, such weight loss surgery can be costly. They’re also not risk-free with risks varying greatly depending on the person’s overall health profile and age as well as skill and experience of the surgeon.

As Microbiota – Wikipedia research progresses apace, the future will likely include some form of microbiota intervention to help mediate both weight loss as well as diabetes reversal. However, it’s too soon to know exactly what such interventions might entail.


1. Hilling, Denise E., et al. “Effects of donor-, pancreas-, and isolation-related variables on human islet isolation outcome: a systematic review.” Cell transplantation 23.8 (2014): 921-928. http://journals.sagepub.com/doi/…

2. Sherry, Nicole, et al. “Teplizumab for treatment of type 1 diabetes (Protege study): 1-year results from a randomised, placebo-controlled trial.” The Lancet 378.9790 (2011): 487-497. https://www.ncbi.nlm.nih.gov/pmc…

3. El-Badawy, Ahmed, and Nagwa El-Badri. “Clinical efficacy of stem cell therapy for diabetes mellitus: a meta-analysis.” PloS one 11.4 (2016): e0151938. http://journals.plos.org/plosone…

4. Colquitt, Jill L., et al. “Surgery for weight loss in adults.” The Cochrane Library (2014). http://onlinelibrary.wiley.com/d…


Can the cervical cancer vaccine cause cervical cancer instead? The info has been around various Indonesian WhatsApp groups lately, but I don’t know how to fact check.



Can the cervical cancer vaccine cause cervical cancer instead? The info has been around round various Indonesian WhatApp groups lately, but I don’t know how to fact check.‘.

Given how you framed your question, first a small digression seems necessary. Responding with skepticism to information circulating on local social media shows good judgment IMO. Following up by asking a question on a Q&A forum like Quora is even better.

Social media are excellent tools for personal communication (‘I got home safely’, ‘Looks like my flight is delayed so I’m waiting in front of the boarding gate’) but extremely poor at information sharing. This is because many using them to share information tend to be ill-informed themselves, poorly educated about how to discern rumor from fact and untrustworthy from trustworthy news sources as well as all too glib and careless about what they share.

Scientific and medical information from original, scientifically peer-reviewed sources or from a credentialed entity such as a government agency authorized to do so are more reliable.

No, the cervical cancer vaccines can’t cause cervical cancer. Currently (as of Jan 2018),

  • Approved cervical cancer vaccines (HPV vaccines – Wikipedia) are Gardasil – Wikipedia, made by Merck (1), and Cervarix – Wikipedia, made by GlaxoSmithKline (2).
  • Essentially a mixture of proteins, they contain no live organism so they’re non-infectious and thus can’t induce a chronic infection, which research suggests is necessary for cervical cancer.

At present epidemiology suggests not all but ~90% of cervical cancer is caused by HPV (Human papillomavirus infection – Wikipedia). Specifically, by now numerous epidemiological studies the world over have clearly linked chronic infection with specific types of HPV to cervical cancer (3, 4, 5, 6, 7, 8, 9). HPV is a nonenveloped, double-stranded DNA virus. Thus, the currently approved cervical cancer vaccines target HPV.

The US ACIP (Advisory Committee on Immunization Practices – Wikipedia) provides detailed information (background, recommendations, safety, efficacy and adverse effects) on the cervical cancer HPV vaccines (see below from 10). Key detail to note? The vaccines are composed of envelope proteins from different types of HPV, not the whole virus itself. The cervical cancer HPV vaccines are thus non-infectious and can’t themselves cause either a chronic infection in the short-term nor cervical cancer in the long-term.

An abundance of data thus far from epidemiological follow-up studies in vaccinated populations also suggest these vaccines are both safe and effective. Since the first HPV vaccine was approved in 2006, a steady stream of scientific studies from various countries have confirmed their safety and efficacy, specifically, lower rates of HPV spread in the form of lower rates of genital warts, and lower rates of cervical tissue abnormalities (11, 12, 13, 14, 15, 16, 17).


1. https://www.fda.gov/downloads/Bi…

2. https://www.fda.gov/downloads/Bi…

3. Smith, Jennifer S., et al. “Human papillomavirus type distribution in invasive cervical cancer and high‐grade cervical lesions: a meta‐analysis update.” International journal of cancer 121.3 (2007): 621-632. http://onlinelibrary.wiley.com/d…

4. Koshiol, Jill, et al. “Persistent human papillomavirus infection and cervical neoplasia: a systematic review and meta-analysis.” American journal of epidemiology 168.2 (2008): 123-137. https://pdfs.semanticscholar.org…

5. Ciapponi, Agustín, et al. “Type-specific HPV prevalence in cervical cancer and high-grade lesions in Latin America and the Caribbean: systematic review and meta-analysis.” PloS one 6.10 (2011): e25493. http://journals.plos.org/plosone…

6. Chan, Paul KS, et al. “Meta-analysis on prevalence and attribution of human papillomavirus types 52 and 58 in cervical neoplasia worldwide.” PLoS One 9.9 (2014): e107573. http://journals.plos.org/plosone…

7. Guan, Peng, et al. “Human papillomavirus types in 115,789 HPV‐positive women: a meta‐analysis from cervical infection to cancer.” International journal of cancer 131.10 (2012): 2349-2359. http://onlinelibrary.wiley.com/d…

8. Hammer, Anne, et al. “Age‐specific prevalence of HPV16/18 genotypes in cervical cancer: A systematic review and meta‐analysis.” International journal of cancer 138.12 (2016): 2795-2803. http://onlinelibrary.wiley.com/d…

9. Clifford, Gary M., Stephen Tully, and Silvia Franceschi. “Carcinogenicity of Human Papillomavirus (HPV) Types in HIV-Positive Women: A Meta-Analysis From HPV Infection to Cervical Cancer.” Clinical Infectious Diseases 64.9 (2017): 1228-1235. https://pdfs.semanticscholar.org…

10. Markowitz, Lauri E., et al. “Human papillomavirus vaccination: recommendations of the Advisory Committee on Immunization Practices (ACIP).” MMWR Recomm Rep 63.RR-05 (2014): 1-30. https://www.cdc.gov/mmwr/pdf/rr/…

11. Brotherton, Julia ML, et al. “Early effect of the HPV vaccination programme on cervical abnormalities in Victoria, Australia: an ecological study.” The Lancet 377.9783 (2011): 2085-2092. http://adispne.fr/wp-content/upl…

12. Howell-Jones, Rebecca, et al. “Declining genital warts in young women in England associated with HPV 16/18 vaccination: an ecological study.” The Journal of infectious diseases 208.9 (2013): 1397-1403. https://pdfs.semanticscholar.org…

13. Mesher, D., et al. “Reduction in HPV 16/18 prevalence in sexually active young women following the introduction of HPV immunisation in England.” Vaccine 32.1 (2013): 26-32. https://ac.els-cdn.com/S0264410X…

14. Drolet, Mélanie, et al. “Population-level impact and herd effects following human papillomavirus vaccination programmes: a systematic review and meta-analysis.” The Lancet infectious diseases 15.5 (2015): 565-580. http://www.10annivaccinohpv.it/i…)

15. Bollerup, Signe, et al. “Significant reduction in the incidence of genital warts in young men 5 years into the Danish human papillomavirus vaccination program for girls and women.” Sexually transmitted diseases 43.4 (2016): 238-242.

16. Ferris, Daron G., et al. “4-Valent Human Papillomavirus (4vHPV) Vaccine in Preadolescents and Adolescents After 10 Years.” Pediatrics (2017): e20163947.

17. Kjaer, Susanne K., et al. “A 12-year follow-up on the long-term effectiveness of the quadrivalent human papillomavirus vaccine in 4 Nordic countries.” Clinical Infectious Diseases (2017).


Does playing in the dirt help kids develop a strong immune system?



Does playing in the dirt help kids develop a strong immune system?‘.

Rather than playing in dirt per se, growing up in ‘natural’ environments helps kids develop a balanced immune response while strength is an unhelpful gauge of immune system function. This answer clarifies

  • How exposure to dirt became associated with immune system functioning.
  • Why rather than strength, whether or not an immune response is orderly/well-controlled is a more appropriate gauge for assessing immune response outcome.
  • Why it’s more accurate to consider ‘playing in the dirt’ not literally but rather as a metaphor for a more consciously ‘natural’ living.

How did the notion of playing in the dirt get linked to immune system function? Steadily through the 20th century til date, epidemiologists noticed a sharp uptick in rates of a variety of chronic inflammatory disorders such as allergies and autoimmunities in Developed country – Wikipedia, meaning throughout Western Europe, North America and Australia.

Such abrupt onset and spread of non-infectious diseases within a mere generation or two made purely genetic causes such as mutations less likely. The timeline instead fingered as-yet unidentified environmental factors. What could they be?

In 1989, the epidemiologist David Strachan observed a tendency for younger siblings within large families to be much less predisposed to allergies such as hay fever and eczema. Specifically, the record suggested protection for younger siblings who developed a series of childhood infections (1). This implied a role for childhood infections in resistance to allergies.

Around the same time, multiple studies started correlating resistance to allergy and autoimmunity with childhood exposure to farms or farm living (2). The link between farm living and protection against chronic inflammatory disorders brought to focus environmental factors associated with farms, obviously dirt and plenty of it as well as poop and plenty of it (see below from 2).

The link with poop coincided with the discovery of the importance of Microbiota – Wikipedia in human physiology, which thus expanded the ambit from infections to microbes in general.

In recent decades such observations thus helped narrow down environmental factors to microbiota. Specifically, ‘Western’ living typically entails,

  • Few people in these countries live on farms.
  • Indoor sanitation and piped chlorinated drinking water are standard.
  • Exposure to antibiotics and a wide variety of antiseptic agents (cleaners, wipes, lotions) is widespread and frequent.
  • Hospitalized births are standard and increasingly those births are C-section.

Thus, excessive hygiene, especially in childhood, leads to an abrupt and sharp decline in natural exposure to all sorts of microbes. The gist of such observations became codified as the Hygiene hypothesis – Wikipedia, that ‘Western’ lifestyle increasingly automatically undermines natural exposure to microbes. This in turn fundamentally alters how the immune system gets ‘trained’ during formative years and thus increases the risk for inflammatory disorders. How exactly this happens remains the focus of intense research.

What is a strong immune system? Strength of the immune system is inadequate to the task of properly assessing immune function since someone with autoimmunity has a demonstrably strong immune system. Similarly, someone with allergy makes demonstrably strong immune responses to Antigen – Wikipedia perceived as innocuous by others. Rather than strength, disorder or dysregulation sets apart immune system function in inflammatory disorders. Thus, it’s more accurate and appropriate to focus on how the immune system functions, orderly or disorderly, rather than its strength.

Why playing in the dirt is better considered a metaphor for more natural living. Since time immemorial, humans have had interactions with the natural world which included children playing in the dirt. As outlined above, the Industrial Revolution – Wikipedia created a schism by making possible living that represents a drastic difference in kind from that past. However, it did so at the expense of the environment with clean air, water and soil its prominent casualties. Industrialization ended up desecrating and polluting vast tracts of the land all around us, especially urban lands. In many places, the land has become polluted with toxic products of industrial runoff, lead being a case in point. As a 2015 report notes (see below from 3),

‘Urban soil has become severely lead contaminated, especially in inner cities (Filippelli and Laidlaw 2009; Mielke et al. 2013).’

Thus, when it comes to playing in the dirt, discretion becomes the better part of valor with parents and caregivers taking care to ensure the ‘dirt’ children play in is really wholesome dirt and not soil that in the past was subjected to industrial activity. Deliberately choosing several other options and activities would also help ensure children develop the ability to make balanced immune responses.

  • Reducing exposure to unnecessary antibiotics and antiseptic agents.
  • Choosing C-section only when medically necessary and not as an elective.
  • Frequent exposures to farm environments, for example frequently visiting petting zoos and keeping pets at home.
  • Spend more time outdoors in natural environments, more pristine the better, national parks being case in point.
  • Feeding a diet largely composed of fruits and vegetables with plenty of natural fibers while avoiding processed foods as much as possible would help children develop and sustain the type of diverse microbiota associated with health.


1. Strachan DP (1989) Hay fever, hygiene, and household size. BMJ 299, 1259–1260. https://www.ncbi.nlm.nih.gov/pmc…

2. Kabesch, Michael, and Roger P. Lauener. “Why Old McDonald had a farm but no allergies: genes, environments, and the hygiene hypothesis.” Journal of leukocyte biology 75.3 (2004): 383-387. https://www.researchgate.net/pro…

3. Mielke, Howard W. “Soils and Health: Closing the Soil Knowledge Gap.” Soil Horizons 56.4 (2015). https://dl.sciencesocieties.org/…