Paul Has Measles is a children's book about viruses and vaccines available in English (download pdf) Spanish (download pdf) French (download pdf) German (download link) Portuguese (download pdf) Romanian (download pdf), Italian (download pdf), Croatian (download pdf) Mixtec (download pdf) Hindi (download pdf) Russian (download pdf) Japanese (download pdf) Nahuatl (download pdf) Arabic (download pdf) Chinese (download pdf) and Mayan (download pdf). Kindle and paperback versions also available at Amazon in English, Spanish, French.

Nipah virus at 20

Nipah virus This week I attended the Nipah Virus International Conference in Singapore, marking the discovery of the virus 20 years ago. It’s an opportune time to recall the events around the emergence of this deadly pathogen.

An outbreak of respiratory disease and encephalitis in pigs during 1998 took place in Ipoh City of Perak state in Malaysia (illustrated), and was followed by lethal encephalitis in patients associated with pig farming. Initially the pig disease was thought to be caused by classical swine fever virus, while the human disease was considered a result of infection with Japanese encephalitis virus (JE). Measures were taken to reduce mosquito populations by spraying, and immunizing workers with a JE vaccine. Neither measure slowed the epidemic.

By the end of 1998 the outbreak spread to Sikimat in Negeri Sembilan. The next year the disease spread to abattoir workers in Singapore. The movement of the disease was a consequence of transport of pigs from farm to farm in Malaysia, and to a slaughterhouse in Singapore (we now understand that most infected pigs do not show signs of disease). The outbreak in Malaysia ended when 1.1 million pigs were culled, and disease in Singapore stopped when importation of pigs from Malaysia was halted. A total of 283 human cases with 109 fatalities (39% fatality) was recorded.

A key player in the discovery of the cause of this outbreak was Kaw Bing Chua, who at the time was working at the University of Malaya. Chua had been working as a medical doctor until his 40s when he became frustrated with the profession. He was given a laboratory position at the University of Malaya and was there when the pig epidemic broke. His superiors thought the causative agent was JE virus but Chua thought otherwise. However because he had little virological experience he was ignored. Chua inoculated cell cultures with cerebrospinal fluid from one patient and observed the formation of syncytia, which would not be expected of JE virus. He brought the virus to the CDC at Ft. Collins, CO, which had responsibility for arboviruses. Work done there showed that the virus was not JE, and an electron micrograph suggested the presence of a paramyxovirus. Consequently the project was shifted to CDC in Atlanta, GA for further study.

Several years earlier (1994) an outbreak of respiratory and neurological disease in Australian horses and their trainers was ascribed to a Hendra virus, a newly discovered paramyxovirus. Given the similar disease in Malaysia and Singapore, experiments were done to determine if antibodies to Hendra Virus reacted with Chua’s virus. The results showed that the Malaysian outbreak was due to a new Hendra-like virus, subsequently named Nipah Virus after the town of Kampung Sungei Nipah. There lived the patient whose CSF yielded the first virus isolate.

It was subsequently determined that Nipah virus had spilled over into pigs from its natural reservoir, fruit bats of the Pteropid species. Deforestation for pulpwood and industrial plantations in the previous 20 years had reduced the habitat of these bats. The severe haze that was a consequence of burning forests further reduced the ability of flying foxes to forage in fruit trees. Meanwhile, farmers had established piggeries in fruit tree orchards. Flying foxes attracted to these trees either contaminated pigs directly with virus-laden urine and feces, or dropped partly eaten and contaminated fruit on the ground which was then eaten by pigs. The pigs became infected and then passed on the virus to humans.

After this first Nipah virus outbreak, no subsequent infections of pigs in Malaysia or Singapore were reported, likely due in part to measures taken to improve biosecurity on pig farms to reduce the introduction of virus by flying foxes. However outbreaks of lethal Nipah Virus disease subsequently took place in Bangladesh and India. In the former country, infections were associated with consumption of contaminated date palm sap into which virus had been introduced via bat excreta. Infections in India are not associated with consumption of date palm sap, and the risk factors remain to be identified.

While Nipah virus infections continue to occur in India and Bangladesh, there are relatively few cases. Nevertheless, given the wide geographic distribution of fruit bats harboring the virus, and the absence of licensed vaccines and therapeutics, Nipah virus has been identified by WHO as one of 8 viruses with the potential to cause a public health emergency. As revealed at the Nipah Virus International Conference in Singapore, remarkable progress has been made on the development of vaccines and therapeutics. Nevertheless, a great deal of work remains to be done to establish rapid diagnostic tests, and to understand the factors that drive spillover of the virus from bats to humans and other animal species.

By David Tuller, DrPH

What’s going on at the Mayo Clinic? It has been more than two years since the US Centers for Disease Control and Prevention (CDC) removed cognitive behavior therapy and graded exercise therapy as treatments of choice for the illness it now calls ME/CFS. And Mayo still seems not to have noticed that anything has changed—unlike Kaiser Permanente, for example, which acknowledged earlier this year that it had been wrong about the illness.

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Vincent speaks with Félix Rey about his career and his work on solving structures of a variety of viruses and the insights learned about viral membrane fusion and antibody-mediated neutralization.

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By David Tuller, DrPH

Earlier this week, Dr Fiona Godlee, editorial director of BMJ, e-mailed me in response to concerns expressed about the study of the Lightning Process published in Archives of Disease in Childhood, one of the journals under her purview. Those concerns were expressed in an open letter to her signed by 72 scientists, clinicians and other experts, along with more than 60 patient and advocacy organizations.

I sent that letter to Dr Godlee in late November. I had previously sent her the letter, with fewer signatories, in July. She had not previously responded.

Dr Godlee’s letter to me is below. It is disappointing, if not particularly surprising. In this case, BMJ’s abdication of its editorial obligations continues.

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A Vaccine for Every Cold

Avaby Gertrud U. Rey

It is cold outside. My throat is scratchy, I can’t stop sneezing, and I have a runny nose. These are the typical symptoms of a human rhinovirus (HRV) infection, better known as the common cold. The average adult suffers from two to four colds a year, while the average child can experience up to ten infections per year, causing a substantial economic and public health burden.

There are three species of HRV – species A, B, and C. Because these encompass about 170 different strains with relatively little cross-protective immunity between them, a preventative vaccine for HRV has historically been viewed as virtually impossible to achieve. An effective vaccine would have to be multivalent, meaning that it would have to contain antigens for many different strains. The number of antigenic strains that a vaccine can contain is limited by the volume of fluid that can be injected into a patient (typically 0.5 ml for an adult) and the concentration of antigens that can fit into that volume. Many vaccines also contain an adjuvant, an agent that enhances and/or prolongs the immune response to an antigen. Adding an adjuvant to a vaccine further limits the number of antigens an injectable volume can hold.

Because of these limitations, multivalent vaccines are usually trivalent or quadrivalent at most, containing antigens for three or four strains. However, recent progress in technology has allowed for production of vaccines with higher valencies. For example, Merck’s human papillomavirus vaccine, Gardasil 9, protects against nine different viral strains, while the pneumococcal vaccine, Pneumovax 23, protects against 23 different bacterial strains.

These advances in multivalent vaccine science have inspired renewed efforts towards production of a rhinovirus vaccine. A group at Emory University recently showed that intramuscular administration of multivalent HRV vaccines that contain a sufficiently high concentration of formalin-inactivated HRVs can induce neutralizing (i.e., virus-inactivating) antibodies to most, if not all injected antigens.

Initial experiments in mice with high concentration 10-valent and 25-valent vaccines were promising. A first dose of the 10-valent vaccine induced neutralizing antibodies to five out of ten strains, while a booster dose induced neutralizing antibodies to all 10 strains. The 25-valent vaccine induced neutralizing antibodies to 18 out of 25 strains after a first dose and to 24 out of 25 strains after a booster dose.

To be able to increase the number and concentrations of antigens in one injectable dose, the authors next used rhesus macaques as an animal model, where a larger inoculum volume could be used. Immunizing two animals with a first dose of a 25-valent vaccine induced neutralizing antibodies against 24 out of 25 strains in one animal and against all 25 strains in the second animal. A booster dose of this vaccine produced neutralizing antibodies against all 25 strains in both animals. A first dose of a 50-valent vaccine in two additional animals induced neutralizing antibodies towards 41 and 45 of the input strains in the two animals respectively, while a booster dose increased this number to 49 out of 50 strains for both animals. The authors speculate that the greater breadth of response observed in macaques compared to mice following a first dose may be because of animal species differences or because macaques can receive higher input concentrations due to their size, enabling a larger inoculum volume.

The study had a few limitations. First, none of the formulations included HRV C antigens, which are particularly important for pediatric populations. Second, although the authors mention that the booster dose of the 10-valent vaccine caused serum antibodies to persist in mice for 230 days after the boost, they offer no additional information about whether these antibodies persisted beyond this time and whether antibodies produced from any of the other vaccines showed the same level of persistence. Third, the antibody responses were type-specific and not cross-neutralizing, meaning that an antibody produced in response to one antigenic strain only recognized that specific strain. Nevertheless, other studies suggest that even in the absence of cross-reactive antibodies, cross-reactive CD8 T cells can promote clearance of virus. Fourth, intramuscular administration of inactivated HRV only induces serum antibodies and does not usually induce mucosal immune responses, which are important as a first line of defense in protecting the upper respiratory tract against HRV infection.

Furthermore, because mice and rhesus macaques don’t have a cell surface receptor that binds HRV, the authors were unable to perform challenge studies, meaning that they could not infect the immunized animals with live virus to see whether vaccination was effective in preventing disease. Also, animal models are often not fully predictive of outcomes in humans, a phenomenon humorously described by Marc Girard and Stanley Plotkin as “mice lie and monkeys exaggerate.” Therefore, the true efficacy of any vaccine in humans can only be measured by doing human challenge studies.

In spite of its constraints, this study suggests that it is possible to produce a broadly neutralizing vaccine against many different types of HRV by using a simple vaccine approach. The authors hope to produce an adjuvant-containing 83-valent HRV A formulation that can be administered in a 0.5 ml dose. Hopefully, this will bring us one step closer to preventing the common cold.

By David Tuller, DrPH

Last last month, I resent Dr Fiona Godlee a letter criticizing BMJ’s decision to republish the Lightning Process study with the same findings. The first iteration, in July, was signed by 55 scientists, clinicians and other experts. This version was signed by more than 70 experts and over 60 patient and advocacy organizations. After I sent the previous version, more than a dozen of the signatories followed up with letters of their own to Dr Godlee.

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By David Tuller, DrPH

Professor Jonathan Edwards posted this essay a while ago on the Science For ME forum. I only noticed it recently. Professor Edwards, a retired rheumatologist from University College London, has played a key role n the last few years as an advocate for patients as well as proper science. So I thought it would be helpful to share his thoughts on a topic we all wonder about: “What is ME?”

I am reposting this with Professor Edwards’ permission. The views expressed are obviously his.

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From the 22nd meeting of the European Society for Clinical Virology in Copenhagen, Vincent speaks with Thea, Heli, Kim, Caroline and Irma about big data and its increasing use in virology diagnostics, epidemiology, and public health.

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Rich joins Nels and Vincent for a debriefing on the 4th Ringberg Symposium on Giant Virus Biology in Tegernsee, Germany.

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From the Fourth Symposium on Giant Virus Biology in Germany, Vincent, Rich, and Nels speak with Assaf, Stephen, and Alexandra about their careers and their work on giant viruses that infect ocean hosts: Emiliana huxleyi, Aureococcus anophagefferans, and a choanoflagellate.

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