Erratic performance from some Indian-made vaccines
NEW DELHI––Erratic performance from some Indian-made vaccines may be undercutting foot-and-mouth disease eradication efforts throughout the developing world, potentially threatening the lives of millions of cattle, sheep, pigs, and other hooved animals.
The alleged vaccine failures might also pose a significant threat to animals in Europe and North America. Foot-and-mouth disease can travel with infected livestock who are believed to have been vaccinated but have not yet presented symptoms; with infected animal products and byproducts; and even on the wind, as in 2001, when Britain killed more than five million animals to stop an outbreak that blew in from North Africa.
“Kill the messenger!”
Instead of demonstrating to global expert satisfaction that the suspect vaccines work as advertised, however, the Indian Council of Agricultural Research appears to be hellbent on destroying the credibility of Indian Veterinary Research Institute microbiologist Bhoj Raj Singh, whose investigation of vaccine failures in November 2014 brought focus to questions raised for at least two years by recurring foot-and-mouth outbreaks among vaccinated livestock.
While Singh’s findings have not yet been published in peer-reviewed veterinary journals, Singh has since November 2014 posted detailed accounts of his findings and research methods to several credible open-access media for sharing academic papers.
Singh also has significant professional credentials, having headed the National Salmonella Center in Bareilly, India, from 2000 to 2005, and having headed the animal science department for the Port Blair, Andaman and Nicobar islands in 2007-2008.
Singh was subsequently assigned to the Indian Council of Agricultural Research, where he was when he first distributed his controversial FMD vaccine testing report (September 2014 to October 2014).
According to Signh, “Vaccine samples (from 52 batches) [were] officially collected and received from the producers,” including Indian Immunologicals, Intervet India, and Brilliant BioPharma.
“None of the 52 batches of foot-and-mouth disease vaccines of any of the three manufacturers,” Singh found, “had desired emulsion stability and all 10 batches tested for sterility failed” to meet “standards and ethics of vaccine production.”
Further, Singh suggested, “There seems to some problem at the vaccine bottling level, as different vials of the same batch were not uniform in emulsion quality. As no adverse report about vaccine quality has been made by the institute entrusted for monitoring the quality of foot-and-mouth disease vaccine,” Singh continued, it is in his view “evident that there is some major flaw with the testing laboratory’s procedures.”
The flaw, Singh believed, was that “The testing laboratory used only 3-5 vials per batch (since the start of the program) of vaccine, instead of more than 20 vials,” as required under international vaccine testing protocols.
“Poor quality vaccines might be responsible”
Concluded Singh, “Poor quality of foot-and-mouth disease vaccines might be responsible for the series of outbreaks encountered in vaccinated populations in different parts of the country, and poor quality vaccine might be held responsible for huge economic losses incurred by farmers and livestock owners due to mortality of their precious animals and production losses in lactating animals.”
Foot-and-mouth disease reportedly killed 15,230 cattle in Karnataka state, India, in 2013 alone. Infected cattle are not routinely killed in India, as has long been the practice in much of the rest of the world.
In addition to the alleged issues with the quality of the vaccines themselves, Singh noted, “Intervet India is using enerofloxacin as preservative instead of thiomersol. Enerofloxacin is an antibiotic licensed only for therapeutic use till date and therapeutic use of this antibiotic is not recommended in food animals and food-producing animals.”
This is because, Singh said, of “several reasons associated with emergence of drug-resistant microbes causing life threatening infections in animals and human beings. As per guidelines, Enrofloxacin should not be used in dairy animals and even may not be stored in dairy farm drug cabinets. Therefore, use of enerofloxacin as preservative in foot-and-mouth disease vaccine intended to be used in ruminants needs careful review.”
Internationally noted for foot-and-mouth disease research, Louisiana State University professor emeritus Martin Hugh-Jones is now a moderator for ProMED-mail, the information exchange network for the Program for Monitoring Emerging Diseases.
“Logically,” Hugh-Jones told ANIMALS 24-7, “the Indian government should forward test samples of the relevant vaccines to the Pirbright Institute for Animal Health,” the British laboratory long considered the world leader in foot-and-mouth disease study, “for confirmatory testing, along with any vials left in Singh’s laboratory.”
Instead, reports by G.S. Mudur of The Telegraph, Amitabh Sinha of The Express, and Vishwa Kundapura of The Hindu indicate, the Indian Council of Agricultural Research appears to be more concerned with squelching Singh’s criticisms than with disproving them.
Singh is sued
Wrote Murdur on May 28, 2015, “The Union agriculture ministry is probing the circumstances under which a senior government scientist purportedly tried to malign vaccines used to protect livestock from foot-and-mouth disease outbreaks. An expert panel from the Indian Council of Agricultural Research has told the agriculture ministry that Bhoj Raj Singh, has ‘caused damage’ to the reputation of India’s foot-and-mouth disease control program by raising unsubstantiated claims about its vaccines,” never mind that Singh presented his evidence in considerable technical detail.
Singh, Mudur continued, “now faces a lawsuit from India’s largest supplier of foot-and-mouth disease vaccines,” in part because his findings were printed out on letterhead before he posted them, causing Singh’s account “to resemble an official government document with the words ‘Government of India, Ministry of Agriculture’ at its top.”
Mudur said Singh’s findings “surprised sections of Indian Council of Agricultural Research scientists and the vaccine manufacturers, including Indian Immunologicals Limited, a wholly owned subsidiary of the National Dairy Development Board that has orders to supply about 200 million of the 328 million foot-and-mouth vaccine doses the control program will use in 2015-16.”
Indian Immunologicals also exports foot-and-mouth vaccines. Wrote Murdur, “Two IIL officials, who requested anonymity, said they suspected the company had lost an order from Sri Lanka after Singh posted his report.”
“Countries will have reason for worry”
Explained Indian Immunologicals managing director Kollengode Balasubramaniam, “This is an airborne, trans-boundary disease. Countries that are already free of foot-and-mouth disease will have reason for worry if it is shown that India’s control program is poorly managed.”
The Indian Council of Agricultural Research, “prompted by Singh’s report,” Mudur said, “had asked a three-member panel to conduct quality tests on the foot-and-mouth disease vaccines and investigate Singh’s role in posting the report on a website without internal consultations.”
But the three-member panel, chaired by Indian Council of Agricultural Research additional director-general Gaya Prasad, was scarcely an independent external review, open to international scientific scrutiny.
The panel asserted, according to Mudur, that “Singh’s report on the vaccine samples’ stability and sterility was based on tests conducted by ‘inexperienced laboratory workers’ who did not follow the established protocols. In its report submitted to the ministry in January,” Mudur continued, “the panel said the test results were ‘highly questionable’ as the same batches of the foot-and-mouth disease vaccine had passed sterility tests at the Indian Veterinary Research Institute.
Panel findings disputed
“Singh told this newspaper,” Mudur continued, that “he had informed the agriculture ministry about the test results before posting them on the website. He claimed the Indian Council of Agricultural Research panel had asked the three manufacturers to provide fresh batches of the vaccines, rather than test the vaccines that had already been released in the field. In a subsequent post on a social networking website for researchers, Singh said it appeared that the ICAR panel “wanted to give opportunity to the firms to produce good quality vaccine,” instead of examining potentally problematic batches.
The panel went on to describe the Singh report as a “fraudulent,” based on “scientifically and technically unsound” data, and recommended that “such unscrupulous scientists… holding responsible positions must be punished appropriately so that such deliberate acts of mala-fide are prevented in future.”
The primary concerns of the panel, Murdur indicated, was that “Singh’s report may hamper vaccine exports by the Indian manufacturers.”
“Wherever we’ve introduced the vaccine,” Prasad told Murdur, “foot-and-mouth disease outbreaks have declined. This pattern is clear.”
The vaccines work––but consistently?
But the questions raised by Singh and by alleged vaccine failures in the field do not pertain to whether the Indian-made foot-and-mouth disease vaccines work at all. Rather, the focal issue is whether the vaccines work consistently enough for the users to be certain that foot-and-mouth disease outbreaks will not continue to occur despite intensive vaccination campaigns.
Observed Mudur, “The foot-and-mouth disease project directorate’s 2013-14 annual report says that nearly 50% of foot-and-mouth outbreaks in India occurred in Andhra Pradesh, Karnataka, Kerala, and Tamil Nadu. These four states are fully covered by the foot-and-mouth disease control program.”
“Room for concern”
“It remains to be seen if Singh’s claims are indeed “unsubstantiated” or ‘fraudulent,’” ProMED-mail animal disease and zoonoses moderator Arnon Shimshony told ANIMALS 24-7. “The spread of foot-and-mouth disease in India in 2014, in spite of claimed vaccination, left room for concern. Since the Indian strain reached Tunisia and Algeria, in North Africa, where Indian vaccines were applied, the issue is not restricted to India.”
Vaccine failures were in April 2015 blamed for recurring foot-and-mouth disease outbreaks in five adjoining provinces of northwestern Algeria where vaccination campaigns had been conducted in 2014: El Bayadh, Saida, El Oued, Ghardaia, and Sidi Bel Abbes (3, 20, 22, 32, and 47 on the accompanying map).
Responding, Algerian agriculture minister Abdelwahab Nouri temporarily closed the livestock markets in the afflicted regions, imposed quarantine and transport restrictions on live animals, and ordered the governors of 45 of the 48 provinces “to undertake a new vaccination campaign against foot-and-mouth disease,” reported Ben Mohamed Assem of the multimedia news portal Ennahar.
The vaccination campaign was to “cover all sheep, goats and cattle aged three months or more, even if they have already been vaccinated,” Abdelwahab Nouri stipulated.
Exempted were only three of the most remote and sparsely populated provinces: Adrar, Illizi, and Tindouf provinces (1, 33, and 37 on the map).
Keeping the cold chain
Earlier, apparent foot-and-mouth disease vaccine failures in Algeria were attributed chiefly to lapses in keeping the vaccine vials continuously refrigerated, called in epidemiologal jargon “breaks in the cold chain.”
Explained Shimshony and Abdelali Benkirane, of the Institut Agronomique et Veterinaire Hassan II in Rabat, Morocco, in an August 2014 ProMED post, “The vaccine is delivered in 250 milliliter vials. If a cattle dose contains five milliliters, a vial is to be used for 50 head. Vets will obviously open a vial in a premise, not use it up, then transport it long distances and re-use it.
“Hopefully this will not have much effect on the potency of an inactivated vaccine, Shimshony and Benkirane wrote. “However, what about the effect on the adjuvant?”
An adjuvant is a substance added to a vaccine to enhance the immune response of the vaccinated individual. Even if a vaccine remains potent, adjuvant failures can result in erratic vaccination results.
Foot-and-mouth disease may be the most prominent of the many diseases covered by internationally enforced policies against importing or exporting vaccinated animals. These policies exist because of the difficulty of distinguishing animals who have been vaccinated from animals who have developed antibodies from actual exposure to a disease, and may therefore pass the disease along.
Far more animals have been culled in response to the H5N1 avian flu virus than in response to all other disease outbreaks combined, with other highly pathogenic avian influenzas among the runners-up, but foot-and-mouth disease has led to culling the most mammals.
Recounted Shimshony in 2013, “Until 1991 mass vaccinations against foot-and-mouth disease were annually applied in European Union member countries including Germany, France, the Netherlands, Belgium, Spain, and Italy, with satisfactory results. Under pressure of nations including the United Kingdom, Denmark, and Ireland, this was discontinued. Imports of vaccinated animals and their products into the EU were banned,” in favor of “stamping out” disease outbreaks by attempting to cull all potentially exposed animals.
“Some traumatic experiences since––in particular, the 2001 foot-and-mouth disease epizootic in the United Kingdom and some continental EU countries––contributed to significant changes in public opinion regarding the non-vaccination, stamping-out policy,” Shimshony continued.
The 2001 foot-and-mouth disease strain reached Britain after hitting at least 25 other nations, beginning in 1990, when it was identified in northern India. The Pan-Asian strain, as it was called, surged across India with the illegal traffic in cattle for slaughter in the southern state of Kerala, then east, reaching Taiwan by 1999. It spread west into Saudi Arabia, Turkey, and eastern Europe in waves coinciding with the annual haj pilgrimage to Mecca.
Eventually, after exploring the theory that the Pan-Asia foot-and-mouth strain reached Britain via food waste from a freight ship, many British and American scientists concluded that it more likely reached Britain as result of a sandstorm that swept northern Africa in mid-February 2001. Satellite photos showed that dust from one of the hardest-hit areas in North Africa settled in Britain seven days later––seven days before the outbreak was identified in Britain.
Foot-and-mouth disease was eradicated from Britain by the end of 2001, for at least the third time in 80 years, by killing every hooved animal on 9,677 farms, including 4.9 million sheep, 763,787 cattle, and 428,000 pigs.
Underscoring the magnitude of the slaughter, the Latin word “decimation” literally means killing one animal or human in ten. The British cull of hooved livestock was one in six: nearly double decimation.
Britain had only just completed culling 3.5 million cattle, over 15 years, to stop the spread of mad cow disease. Believing that effort to have been successful, albeit against a much less contagious disease transmission agent, British authorities rejected the use of vaccination to contain the Pan Asian foot-and-mouth disease outbreak, because vaccinated animals as well as diseased animals were, and are, banned from European commerce.
But rejecting vaccination proved to be a strategic mistake. A vaccination strategy would have ringed infected herds with immune animals before culling began, thereby keeping foot-and-mouth disease from spreading on the wind, on the clothing of workers, or in any other accidental manner. Culling alone did not prevent extensive accidental transmission of Pan Asian foot-and-mouth disease to all parts of Britain before the outbreak was quelled.
Dutch vets revolt
The foot-and-mouth epidemic hit The Netherlands about a month after reaching Britain. Retired small-animal veterinarian Peter Poll, then 68, was recalled from retirement to help direct a vaccination-and-slaughter campaign that eradicated the Dutch outbreak within just two weeks, at cost of 265,000 animals killed––a lot, but a fraction as many as in Britain.
Nonetheless 10,000 animals were killed for every actual case of foot-and-mouth disease detected.
Appalled, Poll and 10 other veterinarians in October 2001 asked the Royal Dutch Veterinary Association to endorse a warning to the Dutch government that they would go on strike rather than ever again kill animals who had already been vaccinated.
Poll et al asked for repeal of the European Union requirement that animals vaccinated against hoof-and-mouth be killed before livestock from that nation can be exported.
As many as two billion poultry and an average of more than a million hooved mammals per year worldwide have been culled during the more than two decades that the EU has prohibited imports and exports of vaccinated animals, animal products, and animal byproducts, including milk, meat, eggs, and leather.
Because the EU and many other nations prohibit imports of products and byproducts from vaccinated animals, the governments of nations that export livestock products and byproducts often simply cull potentially infected animals by any means available, hoping to end the outbreaks by culling alone, without investing in vaccination.
The economic calculation in such instances is that vaccination and culling require about the same amount of time spent per animal to accomplish, but vaccination costs veterinary time, while culling can be done by low-paid farm workers or soldiers.
The South Korean Ministry of Food, Agriculture, Forestry & Fisheries therefore culled more than 1.7 million pigs, cattle, and dogs (believed to be mostly dogs raised for meat) during a two-month foot-and-mouth disease outbreak in 2010-2011.
Most of the pigs were buried alive. Eventually 1.2 million cattle and 210,000 brood sows were vaccinated to end the outbreak, but only after weeks of appeals from international disease control experts and public protests led by the organization Korean Animal Rights Advocacy.
Despite the massacres, South Korea has continued to experience frequent local foot-and-mouth disease outbreaks, and continues to cull whole herds of cattle and pigs to contain them.
Dutch push policy change
Indirectly responding to Poll’s petition a dozen years after Poll et al submitted it, Dutch state secretary of economic affairs Sharon A.M. Dijksma on June 4, 2013 amended Dutch policy to favor vaccination over “stamping out,” and committed The Netherlands to trying to reverse European Union and other international policies which require culling livestock who have been exposed to foot-and-mouth disease, classical swine fever, and other contagious diseases of widespread concern, even if the animals are apparently healthy and have been vaccinated.
If the Dijksma initiative succeeds, it will mean globally that about a million fewer pigs and cattle per year will be raised and killed each year to achieve the same levels of production, because a million a year will not be just culled and burned or buried.
Dijksma pointed out that the difficulty of distinguishing vaccinated animals from those who have been infected by foot-and-mouth disease and classical swine fever has recently been overcome by the introduction of so-called DIVA vaccines.
“DIVA” is short for “differentiating infected from vaccinated animals.” DIVA vaccines are created by engineering them to produce antibodies with slightly different “disease signatures” from antibodies to the actual diseases that the antibodies are designed to fight.
“After emergency vaccination has been applied, two alternatives are possible: either you then destroy the vaccinated animals, or you do not. The latter approach is called vaccination ‘for life,’ and is the option that I prefer,” Dijksma said.
Already, Dijksma said, “Dutch efforts have been partly responsible for a policy change that allows emergency vaccination in Europe in the cases of classical swine fever, foot-and-mouth disease, and avian influenza. This is a relaxation of the former strict non-vaccination policy, but it is still restricted by very specific terms and conditions intended to minimize the risk of spreading of these diseases.”
“The reactions of other EU member states indicate clearly that opinion about emergency vaccination is changing in the right direction,” Dijksma said. “Germany recently laid down a rule that the option of emergency vaccination must be explored before mass destruction of animals may take place, in the case of diseases for which a vaccine exists. The Animal Health Quadrilateral Group, consisting of the U.S., Canada, Australia and New Zealand, has also embraced the strategy of emergency vaccination ‘for life.’”