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Logo of hhspaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
. Author manuscript; available in PMC 2015 Oct 9.
Published in final edited form as:
PMCID: PMC4599698
NIHMSID: NIHMS724114
PMID: 26004568

Deaths following vaccination: What does the evidence show?

1. Background

Modern vaccines are among the greatest public health achievements in history, preventing thousands of illnesses and deaths each year in the United States alone []. However, as illness, disability and death from vaccine-preventable diseases have decreased, concerns over vaccine safety have increased []. Despite the reality that a person is far more likely to be seriously or fatally injured by a disease prevented by vaccines than by a vaccine itself, there appears to be a trend towards increased refusal or delay of recommended vaccinations due to perceived safety concerns [].

During the US multi-state measles outbreak of 2014–2015, most infected persons were not vaccinated against measles or had unknown vaccination status []. Early on, unsubstantiated claims of deaths caused by the measles, mumps, and rubella (MMR) vaccine began circulating on the Internet []. The original claim was based on data from the US Vaccine Adverse Event Reporting System (VAERS). It is important to realize, however, that VAERS is a voluntary reporting system which accepts any submitted report of an adverse event without judging its clinical significance or whether it was caused by a vaccination []. VAERS is a signal detection and hypothesis generating passive surveillance system and therefore any broad claim of cause and effect with respect to deaths following vaccination based on VAERS reports should not be interpreted as proof of causality.

We summarize historical information and published epidemiologic data on deaths following vaccination, including events where reasonable scientific evidence exists to conclude that vaccination caused or contributed to deaths. There are instances where medical errors or other human factors, not the vaccine as it was meant to be used, have caused deaths following vaccination [,]. However, our summary is restricted to deaths possibly related to the vaccine itself.

2. Historical events

In the era of modern medicine, some of the first concerns about vaccines causing death date to isolated, but high profile past vaccine safety incidents. The “Cutter Incident” in 1955 involved a flaw in the Salk polio vaccine manufacturing process at Cutter Laboratories that led to production of substantial amounts of what was thought to be inactivated vaccine that contained live poliovirus. The result has been called “…one of the worst pharmaceutical disasters in US history”[], with 40,000 cases of polio resulting in 51 cases of permanent paralysis and five deaths among vaccinated individuals, and 113 cases of paralysis and five deaths among contacts of vaccinated individuals [,]. As a result of the Cutter Incident, the US government implemented much more vigilant monitoring and regulation of the vaccine industry []. The Food and Drug Administration (FDA) now requires extensive testing to evaluate the safety and efficacy of vaccines prior to licensure. After licensure, FDA requires ongoing lot-release testing and manufacturing facility inspections. Additionally, manufacturers are required to conduct post-licensure safety monitoring for their products and report to the FDA [,].

In 1976, concerns in the United States about a possible influenza pandemic involving a virus similar to the deadly 1918 pandemic strain resulted in a large-scale vaccination program for the entire country. Approximately 45 million people were vaccinated in 10 weeks with what became known as the “swine flu vaccine” []. The US government abruptly stopped the vaccination program when no swine flu cases were detected outside the military base where the disease originated and when an unexpectedly high number of cases of Guillain-Barré syndrome were reported in vaccinated individuals. The vaccine was estimated to have caused approximately one Guillain-Barré syndrome case per 100,000 persons vaccinated [], resulting in 53 deaths []. As a result of the association between the 1976 swine flu vaccine and Guillain-Barré syndrome, this condition is closely monitored every influenza season as part of the influenza vaccine safety monitoring in the United States.

3. Current epidemiologic data on death associated with vaccination

Multiple large reviews and studies have been conducted to evaluate the association between vaccination and death. The results have consistently been reassuring. The Institute of Medicine (IOM) reviewed deaths reported to VAERS after childhood vaccines in the early 1990s []. Some of the reports did not have enough information to make a determination about causality, but among reports with adequate follow-up, the IOM concluded that the vast majority of reported deaths were coincidental and not causally related to vaccination. There was one death due to a vaccine strain viral infection: a 3-month-old infant died from myocarditis after oral polio vaccine (which is no longer licensed for use in the United States) and DTP vaccine; vaccine strain poliovirus was isolated from the child’s myocardium. In another review of 1,266 deaths reported to VAERS from 1990–1997, nearly half of the deaths were due to sudden infant death syndrome (SIDS) with a peak in 1992–1993 and a decline after the “Back to Sleep” campaign was implemented []. The study also found that death reports to VAERS from causes other than SIDS also declined from 1993 to 1996 as the population and the number of vaccines administered increased, which was reassuring. In addition to SIDS, there were multiple causes of death which were not vaccine related, including infectious, congenital, neoplastic, cardiac, and cases with unknown causes due to incomplete information. This review also found that among the death reports, a higher percent of the infants had low birth weight than in the general US population (16.8% vs. 7.2%); lower birth weight infants are known to have higher mortality rates during the first 2 years of life []. Multiple other published reviews of VAERS data for specific vaccines and vaccine types have found no concerning patterns that would suggest a causal relationship between vaccination and deaths [].

In 2003, the IOM examined the relationship between vaccinations and SIDS. The IOM rejected a causal association between the whole cell pertussis-containing vaccine (which is no longer in use in the United States) and SIDS and between exposure to multiple vaccines and SIDS. The IOM concluded that inadequate evidence existed to accept or reject a causal relationship between several other vaccines and SIDS. Additionally, the IOM did “… not recommend a policy review of the recommended childhood vaccination schedule by any of the national or federal vaccine advisory bodies on the basis of concerns about sudden unexpected death in infancy” [].

A study published in 2013 using electronic health record databases reviewed health information on over 13 million vaccinated persons and compared causes of death in the vaccinated study population to the general US population. The death rate 1 or 2 months following vaccination was lower than that in the general US population, and the causes of death were similar []. This study provides convincing evidence that vaccinations are not associated with an increased risk of death at the population level.

4. Evidence in favor of causal associations between vaccination and death

Although the evidence supports the safety of vaccines, there are rare instances where causal relationships between vaccination and death have been established or a plausible theoretical risk exists.

4.1 Anaphylaxis following vaccination

Many vaccines have been determined to rarely cause anaphylaxis. The risk of anaphylaxis is less than two cases per million doses of vaccines administered to children and adolescents []. While anaphylaxis is serious and can be fatal, death and other complications can be prevented with rapid treatment using effective medications including epinephrine, corticosteroids and beta-agonists. A 10-year review of claims to the US National Vaccine Injury Compensation Program noted five cases of death from anaphylaxis after vaccinations []. Another study published in 2003 using electronic health record databases found that after 7,644,049 doses of vaccination in children and adolescents, there were five possible cases of vaccine associated anaphylaxis and none resulted in death []. The Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) recommends screening patients for contraindications and precautions, including allergy history, prior to vaccination []. However, since anaphylaxis following vaccination is not always predictable or preventable, ACIP also recommends that healthcare providers be prepared to treat medical emergencies including anaphylaxis if they occur [].

4.2 Severely immunocompromised persons receiving live vaccines

Live vaccine viruses are attenuated so they do not cause infection in individuals with intact immune systems. Live vaccines, however, are contraindicated for people who are severely immunocompromised [] since their weakened immune systems may result in the live vaccine causing illness. Two published case reports describe immunocompromised children who received varicella vaccine, and where vaccine strain varicella zoster virus infection contributed to their deaths []. In one case, a 4-year-old child who had been in complete remission from acute lymphoblastic leukemia for 5 months received varicella vaccine during a 2-week break from chemotherapy []; in the other case, a 15-month-old did not have a diagnosis of being immunocompromised, but had failure to thrive and several hospitalizations beginning at 5 months of age for infections and respiratory problems requiring steroid treatment [], indicating a possible undiagnosed immunodeficiency. There are at least six case reports of death among severely immunocompromised persons that have been linked to vaccine strain measles virus infection [], including a case of vaccine associated pneumonitis in an immunocompromised person with HIV [] and a case of measles inclusion-body encephalitis in a 21-month-old child with primary immunodeficiency []. CDC recommends screening prior to vaccination so that contraindications and precautions, including previously diagnosed immune system problems are identified [].

4.3 Intussusception after rotavirus vaccine

Intussusception is a rare medical condition in which the bowel folds in, or telescopes, on itself. It can resolve on its own, but might also require medical treatment or in some cases surgery. In very rare instances, it can result in death (less than 1% of cases in developed countries) []. RotaShield®, the first licensed rotavirus vaccine, was withdrawn from use in 1999 after a greater than expected number of reports of intussusception were detected in post-marketing surveillance []. The attributable risk of intussusception was estimated to be one case for every 4,670 to 9,474 infants vaccinated [] and one intussusception death after RotaShield® was reported in the literature []. There is a small increased risk of intussusception associated with the rotavirus vaccines that are currently licensed and in use (RotaTeq® and Rotarix®), but the risk is substantially lower than for RotaShield® at approximately 1 case in 20,000 to 100,000 doses []. One study estimated that among a hypothetical 4.3 million US birth cohort followed to age 5 years, currently licensed rotavirus vaccines prevent 14 deaths, more than 53,000 hospitalizations and more than 169,000 emergency room visits; by comparison the vaccines are estimated to result in an excess of 0.2 deaths, 45 hospitalizations, and 13 short stay visits from vaccine associated intussusception []. A published review of VAERS reports for 2006–2012 for the two currently licensed rotavirus vaccines indicated two death reports from intussusception; however, definitive causal associations with vaccination were not established in either case [].

4.4 Guillain–Barré syndrome after seasonal and 2009 H1N1 (pandemic) inactivated influenza vaccines

Guillain-Barré syndrome is a rare disorder in which a person’s own immune system damages peripheral nerve cells, causing muscle weakness and sometimes paralysis []. Most people recover fully from Guillain-Barré syndrome, but some may have permanent nerve damage. Known risk factors for GBS include bacterial or viral infections, especially Campylobacter jejuni [] and other infections causing diarrhea or respiratory illnesses []. Studies assessing the risk of Guillain-Barré syndrome after seasonal inactivated influenza vaccine since 1976 have shown either no risk or a small increased risk on the order of one to two cases per million doses administered [], which is similar to the risk observed with the 2009 influenza A (H1N1) monovalent vaccine []. However, one study found the cumulative risk of GBS over the entire influenza season was lower in individuals that received 2009 H1N1 (pandemic) inactivated influenza vaccines compared to unvaccinated individuals, indicating that vaccination might prevent GBS cases []. Another study using electronic health record data from 2000 through 2009 found that among 38 confirmed or probable GBS cases that occurred within 6 weeks of seasonal inactivated influenza vaccine, two deaths occurred during a median follow-up time of 6½ months; in neither of the cases that resulted in death was a causal association established with vaccination []. Approximately 5% of Guillain-Barré syndrome cases are fatal [], but given the indeterminate association between influenza vaccination and GBS, risk of death from vaccine-associated GBS would have to be considered theoretical.

4.5 Syncope (fainting) after vaccination leading to head trauma and death

The IOM concluded that the available evidence convincingly supports a causal relationship between the injection of a vaccine and syncope [], although this relationship exists for any medical procedure involving a needle stick (e.g., blood draw). In a study on quadrivalent human papillomavirus vaccine among young women, 15% reported presyncope or syncope after the first dose []. Post-vaccination syncope can result in injuries including head trauma. A VAERS case report described an incident of death attributed to blunt head trauma following a fall secondary to vasovagal syncope that occurred several minutes after vaccination with hepatitis B vaccine []. Syncope is an acute event that typically occurs within 15 minutes of vaccination [], and the Advisory Committee on Immunization Practices suggests a 15-minute observation period after vaccination, especially if the patient is an adolescent [].

4.6 Yellow fever vaccine-associated viscerotropic and neurologic disease

A rare, serious reaction to yellow fever vaccine called yellow fever vaccine-associated viscerotropic disease has similar symptoms to yellow fever illness. Initial symptoms, which usually occur within 1 week of vaccination, are fever, along with feeling generally unwell, muscle pain, nausea, vomiting, and/or diarrhea. These symptoms can progress to multisystem organ failure and death. More than 60 cases worldwide have been reported to CDC and of those, 63% resulted in death []. The incidence of yellow fever vaccine-associated viscerotropic disease in the United States is 0.4 cases per 100,000 doses administered [].

Another rare reaction to yellow fever vaccine is yellow fever vaccine-associated neurologic disease. This includes several conditions, such as meningoencephalitis (inflammation of the brain and its membranes), Guillain-Barré syndrome, acute disseminated encephalomyelitis (inflammation of the brain and spinal cord), and bulbar palsy (paralysis of the motor units of the cranial nerves). Less than one case per 100,000 vaccine doses administered is reported, and it is rarely fatal [].

Both yellow fever vaccine-associated viscerotropic and neurologic disease are more common in in persons aged 60 years or older [], therefore age 60 years or older is a precaution to receiving this vaccine. In the United States, yellow fever vaccine is recommended only for travelers who plan to visit areas where the disease is present and for laboratory personnel who work with yellow fever virus [].

4.7 Complications from smallpox vaccine

Serious adverse reactions and complications from smallpox vaccine can result in death in rare cases []. Based on historical data, the death rate following smallpox vaccination is approximately one death per million persons receiving an initial dose and one death per four million among persons receiving another dose after the first dose []. Death has also occurred among non-vaccinated persons who had accidental contact with vaccination sites of vaccine recipients []. Reactions that can cause or contribute to death include eczema vaccinatum, progressive vaccinia, postvaccinal encephalitis, myocarditis, and dilated cardiomyopathy. Additionally, vaccination of pregnant women can cause fetal infection resulting in stillbirth or infant death [,]. Patients should be carefully screened for precautions and contraindications prior to receipt of smallpox vaccine []. In 2008, a new smallpox vaccine, ACAM2000 replaced the previously used vaccine Dryvax®. The data indicate that ACAM2000 has a similar safety profile to Dryvax® [,]. Naturally occurring smallpox disease has been eliminated worldwide, and in the United States, smallpox vaccine is currently only given to military personnel and selected individuals that might be at high risk of exposure, such as laboratory scientists that work with smallpox or similar viruses [].

4.8 Vaccine-associated paralytic poliomyelitis from oral poliovirus vaccine

Vaccine-associated paralytic poliomyelitis (VAPP) is a rare adverse reaction that can occur in a recipient of oral poliovirus vaccine (OPV) or in a contact of a recipient of OPV []. It can occur in healthy persons and in persons with immune system abnormalities. OPV is no longer used in the Unites States and has been replaced with inactivated poliovirus vaccine, but OPV is still used in many parts of the world. A recent review puts the risk of VAPP at around 4.7 cases per million births with an estimated 498 cases annually worldwide []. VAPP can result in death, but this is rare []. In the United States, from 1980–1989 there were 80 VAPP cases reported and among these reported cases, two patients (3%) died within 60 days after onset of paralysis [].

5. Conclusion

Vaccines are rigorously tested and monitored and are among the safest medical products in use. Millions of vaccinations are administered to children and adults in the United States each year. Serious adverse reactions are uncommon and deaths caused by vaccines are very rare. Healthcare providers can take specific actions to help prevent adverse reactions, including proper screening for contraindications and precautions and observing a 15-minute waiting period after vaccinating to prevent fall-related injuries from syncope. CDC and FDA continuously monitor the safety of US licensed vaccines. All serious VAERS reports, including reports of death, are reviewed. A report is considered serious if at least one of the following is reported: death, life-threatening illness, hospitalization or prolongation of hospitalization, or permanent disability []. In addition, CDC and FDA scientists use statistical techniques to check for disproportional reporting in the VAERS database for deaths and other adverse events for individual types and brands of vaccines []. If CDC or FDA were to detect a potential new safety problem with MMR or any other US licensed vaccine, this “signal” would be further assessed and regulatory and/or public health action would be taken, if necessary.

With respect to the recent claims of deaths caused by MMR vaccine [], drawing broad cause and effect conclusions between vaccination and deaths based on spontaneous reports to VAERS, some of which might be anecdotal or second hand, is not a scientifically valid practice. In fact, a review of the VAERS data reveals that many of the death reports for MMR vaccine involved children with serious preexisting medical conditions or were likely unrelated to vaccination (e.g., accidents). These complete VAERS reports and any accompanying medical records, autopsy reports and death certificates have been reviewed in depth by FDA and CDC physicians and no concerning patterns have emerged that would suggest a causal relationship with the MMR vaccine and death.

The evidence for the safety and effectiveness of vaccines routinely given to children and adults in the Unites States is overwhelmingly favorable. In the case of MMR vaccine, this includes preventing hundreds of potential measles-related deaths each year []. Any discussion of the true risks of vaccination should be balanced by acknowledgment of the well-established benefits of vaccines in preventing disease, disability and deaths from infectious diseases.

Acknowledgments

We gratefully acknowledge Dr. Frank DeStefano for his input and review of this article.

Funding/Support: The review was conducted by the Centers for Disease Control and Prevention (CDC) and no external were used.

Abbreviations

ACIPAdvisory Committee on Immunization Practices
CDCCenters for Disease Control and Prevention
FDAFood and Drug Administration
IOMInstitute of Medicine
MMRmeasles, mumps, & rubella combination vaccine
OPVoral poliovirus vaccine
SIDSsudden infant death syndrome
VAERSVaccine Adverse Event Reporting System
VAPPvaccine-associated paralytic polio

Footnotes

Disclosures: No authors have a conflict of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript.

Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

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51. Shui IM, Rett MD, Weintraub E, Marcy M, Amato AA, Sheikh SI, et al. Guillain-Barré syndrome incidence in a large United States cohort (2000–2009) Neuroepidemiology. 2012;39(2):109–15. [PubMed[]
52. Hughes RAC, Swan AV, Raphaël JC, Annane D, van Koningsveld R, van Doorn PA. Immunotherapy for Guillain-Barré syndrome: a systematic review. Brain. 2007;130:2245–57. [PubMed[]
53. Stratton K, Ford A, Rusch E, Clayton EW, editors. Institute of Medicine. Adverse Effects of Vaccines: Evidence and Causality. Washington DC: National Academies Press; 2011. []
54. Naleway AL, Gold R, Drew L, Riedlinger K, Henninger ML, Gee J. Reported adverse events in young women following quadrivalent human papillomavirus vaccination. J Womens Health (Larchmt) 2012;21(4):425–32. [PubMed[]
55. Woo EJ, Ball R, Braun MM. Fatal syncope-related fall after immunization. Arch Pediatr Adolesc Med. 2005;159(11):1083. [PubMed[]
56. Braun MM, Patriarca PA, Ellenberg SS. Syncope after immunization. Arch Pediatr Adolesc Med. 1997;151(3):255–9. [PubMed[]
57. Gershman M, Staples JE. Yellow Fever Chapter. In: Brunette GW, editor. The Yellow Book. CDC Health Information for International Travel 2014. US Dept. of Health and Human Services. Centers for Disease Control and Prevention; New York: Oxford University Press Inc; 2014. []
58. Staples JE, Gershman M, Fischer M. Yellow fever vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP) MMWR. 2010;59(RR07):1–27. [PubMed[]
59. Casey C, Vellozzi C, Mootrey GT, Chapman LE, McCauley M, Roper MH, et al. Surveillance guidelines for smallpox vaccine (vaccinia) adverse reactions. MMWR. 2006;55(RR01):1–16. [PubMed[]
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The dengue vaccine dilemma

Chris Lo16 December 2019 (Last Updated December 16th, 2019 14:45)

Pharma giant Sanofi has been mired in controversy in the Philippines after allegations that its dengue vaccine Dengvaxia, which had been used in a widespread school vaccination programme, was linked to the deaths of children. Since the vaccine’s ban the Philippines has declared a national dengue epidemic, creating a public health dilemma as infection rates soar.

The dengue vaccine dilemma
Former Philippines President Benigno Aquino III attends the launch of the dengue vaccine in 2016. Credit: Malacañang Photo Bureau

The Philippines is in the midst of a national epidemic of dengue fever, a mosquito-borne tropical disease that causes flu-like symptoms and can be life-threatening, particularly to children if it develops into the more severe form of the disease. The country has attributed at least 622 deaths to the disease this year, a 98% year-on-year increase, prompting authorities to declare a national epidemic in August.

Immunisation rates for dengue in the Philippines have fallen dramatically just a few years after the world’s first dengue vaccination programme – using Sanofi’s live attenuated vaccine Dengvaxia (CYD-TDV) – was rolled out in the country’s schools. Below are the key dates in the rise and sudden fall of Dengvaxia in the Philippines, and the urgent unmet need that still exists in the response to dengue outbreaks.

April 2016: Dengvaxia’s launch in the Philippines

In the spring of 2016, Dengvaxia had a high-profile launch in the Philippines, as the country – having been involved in every phase of clinical development – became the first in the world to access the live recombinant tetravalent vaccine. The Department of Health spent $67m on Dengvaxia and kicked off a mass immunisation programme with the aim of vaccinating a million students by the end of the year.

Sanofi also had high hopes for Dengvaxia, the development of which had taken 20 years and cost around $1.8bn. Officials predicted that the vaccine – which helps protect against all four serotypes of dengue – would drive down infection rates by 24% within the next five years, and Sanofi looked well-positioned to reap the benefits of offering the first-ever dengue vaccine to global markets. By October 2016, Dengvaxia had received regulatory approval from 10 other countries, including Mexico, Brazil and Indonesia.

November 2017: safety concerns after relabelling

More than six months later, after more than 830,000 children had received at least one dose of the vaccine (Dengvaxia is administered as three injections, with six-month intervals), Sanofi announced that it was changing its label to restrict its use to only those who had already been exposed to dengue virus. Having reanalysed its trial results, Sanofi said the evidence now suggested that dengue-naïve people who received the vaccine could be vulnerable to more severe infections.

Some dengue researchers, including a team from the University of Minnesota, said they had long predicted this risk due to the dengue-specific phenomenon of antibody-dependent enhancement (ADE) – the same mechanism that often makes repeat infections more serious. Sanofi argued that ADE might not be the full story, but in the meantime the Department of Health immediately suspended the immunisation drive.

February 2018: a national scandal

Within a few months, the potential implications of the vaccination drive had become a national scandal, and blame was being cast at pharma firms and health department officials alike. Allegations surfaced that the vaccine was linked to the deaths of several children, and in February the Philippines Public Attorney’s Office filed a lawsuit against government officials and executives of Sanofi and distributor Zuellig Pharma. The suit sought damages claiming that a 10-year-old girl died after receiving the vaccine despite the fact that she had a pre-existing condition.

December 2018: European approval

Elsewhere, Sanofi continued seeking regulatory approval for Dengvaxia for use in those who have already been exposed to dengue fever, and in December 2018, the European Commission granted marketing approval for the vaccine to be used in already-exposed individuals aged nine to 45 years and living in dengue-endemic regions.

“In some of the European overseas territories where dengue recurs regularly, people who have had a dengue infection previously are at risk of being infected with the virus again,” said Sanofi Pasteur’s head of global medical affairs Su-Peing Ng. “As the second infection with dengue tends to be more severe than the first, it is important to be able to offer these people a vaccine that could help protect them against subsequent dengue infections,” she said.

February 2019: licence revoked in the Philippines

While Dengvaxia’s use was suspended after Sanofi’s update in November 2017, its long-term future was still in question until February this year, when the Philippines Food and Drug Administration permanently withdrew the vaccine’s licence; the regulator’s director general Nela Charade Puno said the decision had been made because Sanofi failed to comply with its post-marketing commitments.

Meanwhile, the Dengvaxia scandal had by this time become the subject of two congressional inquiries and a criminal investigation. In March, the Department of Justice said it had enough evidence to charge both staff of Sanofi and Philippine health officials, including former Health Minister Janette Garin. The department argued the named defendants had ignored “the identified risks and adverse effects of the vaccine” and were responsible for the subsequent deaths. While a panel of medical specialists are gathering information about the alleged link, to date no conclusive evidence has been presented that connects the deaths to Dengvaxia specifically.

May 2019: US approval

Dengvaxia was approved by the US Food and Drug Administration in May, having been granted a priority review by the agency. Approved under the same restrictions as its licence in Europe, Dengvaxia is authorised for use in dengue-endemic areas of the US, including Puerto Rico, Guam and American Samoa.

August 2019: reviewing Dengvaxia amid an epidemic

With dengue cases surging in the first half of 2019 and Dengvaxia the only approved vaccine option, the Philippine government considered reintroducing the vaccine on the condition that all participants are pre-screened to confirm that they have had previous exposure to dengue.

“If Dengvaxia is proven effective to those who already had dengue in the past, then its application to these individuals will surely cause the decline of the overall number of cases,” said presidential spokesman Salvador Panelo in August.

On 22 August, however, the Department of Health rejected Sanofi’s appeal to overturn the FDA’s ban on Dengvaxia, with the department again citing the company’s failure to submit post-marketing data including risk management plans. A statement by health officials noted that re-approving the vaccine “is for the FDA to act upon”, leaving the door open to a reversal of the decision if Sanofi can satisfy the regulator on its post-marketing work.

September 2019: tough questions

There is currently nothing to suggest that Dengvaxia is linked in any way to the deaths that have been at the centre of the allegations, and the vaccine’s subsequent approval by European and American authorities validates Sanofi’s statements that it is effective and safe when administered correctly.

Nevertheless, the controversy in the Philippines raises troubling questions around the governance of this immunisation drive, and how, despite years of clinical studies, the vaccine was allowed to be administered to those who may have been harmed by it. Without rock-solid safety data and careful management, a vaccination campaign could easily be seen as an exploitative gamble with public safety.

“When you are the first in class, we’re the ones having to develop and understand the science as we go,” Sanofi’s Ng told Reuters in December 2017.

Dengvaxia alternatives

In the meantime, the race is on for an alternative dengue vaccine that overcomes the exposure issue that held back Dengvaxia. Takeda’s candidate TAK-003 is based on an attenuated version of live dengue 2 virus rather than Dengvaxia’s yellow fever, and late-stage trial results earlier this year have demonstrated effective protection against all four dengue serotypes, regardless of previous exposure to the virus.

Another vaccine candidate based on live dengue virus is being developed by scientists at the US National Institutes of Health and the Butantan Institute in Brazil, and licensed to Merck for commercialisation. TV003/TV005 has seen promising results in antibody response to all dengue serotypes and producing T-cell immunity.

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 Date: March 6, 2002

Contacts: Vanee Vines, Media Relations Officer
Chris Dobbins, Media Relations Assistant
(202) 334-2138; e-mail <news@nas.edu>

ANTHRAX VACCINE IS USEFUL,
BUT SHORTCOMINGS UNDERSCORE NEED FOR REPLACEMENT

WASHINGTON -- The current anthrax vaccine is safe and effective, but certain drawbacks - including reliance on older vaccine technology and a six-dose vaccination schedule over 18 months - underscore the need for a better vaccine, says a new report from the National Academies' Institute of Medicine. The current vaccine can continue to be used, but the U.S. Department of Defense should vigorously support research efforts not only to improve the way it is administered, but also to develop an alternative.

The committee that wrote the report did not identify any unexpected short-term adverse reactions to the anthrax vaccine. Furthermore, the rates at which reactions occurred were similar to rates for other vaccines now in use for adults. Scientific data are limited on adverse health effects that might surface months or years following anthrax inoculations, but the evidence available to date does not confirm any long-term health risks among people who have received the vaccine. Because no vaccine is 100 percent safe, however, DOD should create systems to enhance long-term monitoring of health conditions that might be associated with any vaccine given to military personnel.

"The anthrax vaccine should protect against even the inhalational form of the infection, but the lengthy vaccination schedule and the way the shots are physically administered make it far from optimal; it also is manufactured using older technologies that can be improved upon," said committee chair Brian L. Strom, professor of biostatistics and epidemiology, medicine, and pharmacology; and director, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia. "The most prudent course of action is to develop a new vaccine - given the nation's war against terrorism and the domestic attacks where anthrax was used as a deadly weapon. In the meantime, the current vaccine is sufficiently safe and effective to be useful."

The committee pointed out that natural mutations or bioengineered alterations in the anthrax bacteria would not likely produce vaccine-resistant strains. The vaccine acts directly on a toxin from the bacteria, and that toxin must remain unaltered for the bacteria to retain its lethal nature.

ANTHRAX BECOMES A NATIONAL CONCERN

Anthrax primarily is a disease of wild and domestic animals. Historically, humans have contracted it through contact with infected animals or animal products, such as hides contaminated with anthrax spores. Infection occurs when these spores enter the body through inhalation, contact with skin, or ingestion of contaminated meat. However, inhalational anthrax infection had been rare in the United States until the 2001 bioterrorist incidents. Among the people who came in contact with anthrax spores last year, 18 developed confirmed skin or lung infections, leading to five deaths.

Only one anthrax vaccine, referred to as "anthrax vaccine adsorbed" or AVA, is licensed for human use in the United States. At this point, its sole manufacturer is BioPort Corp. in Lansing, Mich. The U.S. Food and Drug Administration approved the vaccine in 1970, largely to protect veterinarians, workers who process animal hair, and scientists working with anthrax. In response to heightened concerns about biological warfare threats during and after the Persian Gulf War, DOD announced in 1997 a plan to vaccinate all U.S. service members to protect them against possible exposure to anthrax bioweapons.

Roughly 2 million doses of the vaccine have been administered, mostly to U.S. military personnel. But some service members have raised concerns about the vaccine's safety and efficacy, and more than 400 military personnel have refused the shots, worried that vaccination could be connected to complaints of chronic fatigue, memory loss, and other health problems. These concerns prompted Congress to request a National Academies study of the vaccine's adverse reactions; long-term health implications; gender differences in reactions; and effectiveness against inhalation exposure.

The report also addresses shortcomings of the manufacturing process and identifies gaps in existing research. It does not examine the military's policy to vaccinate all service members, or consider other populations that could be vaccinated.

A LOOK AT ANTHRAX VACCINE SAFETY

On the whole, the types of reactions associated with the current vaccine and the rates at which they have been observed are comparable to those seen with other vaccines administered to adults, such as the tetanus shot, the report says. Reactions such as skin redness and swelling at the site of the injection are common. Systemic responses - malaise and muscle pain, for example - occur much less often. Reactions may result in time lost from work or brief periods of limited activity, but they do not lead to serious or permanent health impairments. However, women have been more likely than men to experience and report some effects, including swelling and itching at the injection site.

Side effects of the anthrax vaccine, coupled with the required long series of doses, are among the realities that underscore the need for a new and improved alternative, the committee emphasized. Some of the bodily reactions likely stem from the vaccine being injected under the skin rather than into a muscle - which is the typical injection procedure for most vaccines. The anthrax vaccine is given in six shots over 18 months, and an annual booster dose is required. DOD should expedite its research on the anthrax bacteria and disease, and on ways to improve on the current vaccine. A new and improved vaccine should not cause any severe reactions. And among other characteristics, it should require only two or three injections; provide immunity within 30 days that lasts for at least a year; and remain potent for a long period of time so that it can be stockpiled to ensure ample supplies when needed.

The committee evaluated population studies as well as case reports about the safety of the anthrax vaccine. It also heard testimony from those who believe that they or their family members have been harmed by the vaccine. The studies available did not examine vaccination effects in children or the elderly. Although a study is now under way regarding pregnancy outcomes following use of the anthrax vaccine, only limited information exists in this area. The military prohibits giving the vaccine to a woman who knows she is pregnant.

BioPort recently received FDA approval to distribute newly produced anthrax vaccine for the military. Until then, vaccine lots manufactured in the company's renovated facility and filled at another site had not been released pending government approval of plant renovations and satisfactory documentation of the production process. As with all vaccines, government authorities should continue to monitor the company's new batches of anthrax vaccine, the report says.

BROADER RESEARCH EFFORTS NEEDED

More studies using animals are essential for further investigation of the current vaccine's effectiveness and to evaluate any new anthrax vaccines, the committee said. Human studies would not be feasible or responsible.

DOD also should support additional research with laboratory animals on the effectiveness of combining the current anthrax vaccine with antibiotics following inhalation exposure to anthrax spores. These studies should focus on establishing an appropriate time frame for supplemental antibiotic treatment. Limited scientific data now suggest that the vaccine in combination with a 30-day treatment of antibiotics could provide post-exposure protection against inhalational anthrax.

In addition, the report urges the agency to shift its efforts and resources away from specialized programs that review individual reports about adverse events following anthrax inoculations. Instead, the emphasis should be on a broader program for regular analysis of data from the Defense Medical Surveillance System to monitor potential health effects of any vaccine - including the one for anthrax - administered to military personnel. Because these data may point to possible areas of concern and frequently are useful for follow-up analyses of information from civilian reporting systems, DOD also should explore ways to make this information available to civilian researchers.

The study was sponsored by the U.S. Department of Defense. The Institute of Medicine is a private, nonprofit institution that provides health policy advice under a congressional charter granted to the National Academy of Sciences. A committee roster follows.


Read the full text of The Anthrax Vaccine: Is It Safe? Does It Work? for free on the web. Printed copies are available for purchase from the National Academy Press Web site or by calling (202) 334-3313 or 1-800-624-6242. Reporters may obtain a copy from the Office of News and Public Information (contacts listed above).


INSTITUTE OF MEDICINE
Medical Follow-Up Agency

COMMITTEE TO ASSESS THE SAFETY AND EFFICACY OF THE ANTHRAX VACCINE


BRIAN L. STROM, M.D., M.P.H.1 (CHAIR)
Professor of Biostatistics and Epidemiology, Medicine, and Pharmacology;
Director, Center for Clinical Epidemiology and Biostatistics; and
Chair of the Graduate Group in Epidemiology and Biostatistics
School of Medicine
University of Pennsylvania
Philadelphia

WILLIAM E. BARLOW, PH.D.
Senior Scientific Investigator
Center for Health Studies
Group Health Cooperative, and
Research Professor of Biostatistics
University of Washington
Seattle

DAN G. BLAZER II, M.D., M.P.H., PH.D. 1
J.P. Gibbons Professor of Psychiatry and Behavioral Sciences, and Professor of Community and Family Medicine
School of Medicine
Duke University
Durham, N.C.

LINDA D. COWAN, PH.D.
George Lynn Cross Research Professor
Department of Biostatistics and Epidemiology
University of Oklahoma Health Sciences Center
Oklahoma City

KATHRYN M. EDWARDS, M.D.
Professor of Pediatrics and Associate Director
Division of Pediatric Infectious Diseases
School of Medicine
Vanderbilt University
Nashville, Tenn.

DENISE L. FAUSTMAN, M.D., PH.D
Associate Professor of Medicine
Harvard Medical School, and
Director of Immunobiology
Massachusetts General Hospital
Charlestown

EMIL C. GOTSCHLICH, M.D. 1,2
Vice President for Medical Sciences, R. Gwin Follis-Chevron Professor, and Chair of the Laboratory of Bacterial Pathogenesis and Immunology
Rockefeller University
New York City

DENNIS KASPER, M.D. 1
Executive Dean for Academic Programs, William Ellery Channing Professor of Medicine, and Professor of Microbiology and Molecular Genetics
Harvard Medical School, and
Director, Channing Laboratory and Senior Physician
Brigham and Women's Hospital
Boston

DON P. METZGAR, PH.D.
Scientific Consultant
Straudsberg, Pa.

HUGH H. TILSON, M.D., DR.P.H.
Clinical Professor of Epidemiology and Health Policy, and Senior Adviser to the Dean
School of Public Health
University of North Carolina
Chapel Hill

STAFF

LOIS JOELLENBECK, DR.P.H.
Study Director

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Vaccines might have contributed to death of Army reservist

Nov 19, 2003 (CIDRAP News) – A combination of vaccines that included smallpox and anthrax might have contributed to the death of a young Army reservist last April, the Department of Defense (DoD) announced today.

Two panels of civilian experts concluded that the vaccinations might have led to the death of Specialist Rachel Lacy on Apr 4, DoD officials said in a news release. The vaccines included smallpox, anthrax, typhoid, hepatitis B, and measles-mumps-rubella. The Pentagon said Lacy received the vaccines Mar 2 at Fort McCoy, Wis., where her unit was preparing for overseas deployment.

Because Lacy received all the vaccines the same day, the expert panels could not determine which of them might have contributed to her death, DoD said. The panels said that though the evidence "favored a causal relationship," it was not conclusive.

According to DoD's online Smallpox Vaccination Safety Summary, Lacy's case is the first case in the current immunization program in which investigation indicated that the vaccine might have caused death. Four other deaths that followed vaccination have been investigated, the summary says.

Lacy experienced "a complex set of pulmonary, neurological and other symptoms" after the vaccinations, the DoD statement said. "She died due to a severe inflammatory process affecting her lungs, findings consistent with a diagnosis of systemic lupus erythematosus (SLE) or lupus. She did not know she had an underlying immune system disorder, nor did any of her physicians."

Lacy, who came from Lynwood, Ill., was a combat medic with the 452d Combat Support Hospital, which was later deployed to Afghanistan, according to DoD. She died at the Mayo Clinic in Rochester, Minn.

"Specialist Lacy's case was rare and clearly tragic," said Dr. William Winkenwerder, assistant secretary of defense for health affairs. "An important conclusion of both expert groups is that nothing was discovered that indicates our screening programs could have prevented the illness and ultimate death of Specialist Lacy, who had an underlying undiagnosed disorder."

Winkenwerder said DoD would continue its vaccination programs but has asked an advisory panel to evaluate the practice of simultaneous vaccinations. He also commented, "It is important for us to acknowledge the possibility of an association between vaccination and the illness that led to the death of Specialist Lacy. We pledged when we began the vaccination programs to bring the best science to bear in monitoring adverse events after vaccination, and with these reports we are doing this."

More than 900,000 military personnel have been vaccinated against anthrax in the past several years, and more than 500,000 have been vaccinated for smallpox since last December, officials said.

The two expert committees were convened several months ago as part of DoD's surveillance for potential adverse effects of vaccines, officials said. One panel was the Smallpox Vaccine Safety Working Group (SVSWG), a joint subcommittee of the Advisory Committee on Immunization Practices and the Armed Forces Epidemiological Board. (The ACIP advises the Centers for Disease Control and Prevention, while the AFEB advises the DoD.) The SVWSG concluded that "the weight of available evidence favors acceptance of a causal relationship between the immunization experience and the disease" in Lacy's case but does not prove it conclusively, a DoD statement said.

"There's a chance that the immunization experience triggered this disease process," Dr. John Neff, chair of the SVSWG, told CIDRAP News. "There was no evidence that could definitely establish or definitely reject a causal association." Neff is a pediatrician at the Children's Hospital and Regional Medical Center in Seattle.

The other panel was the Clinical Expert Immunization Committee (CEIC), a group of private academic physicians convened by the Health Resources and Services Administration, part of the Department of Health and Human Services. After reviewing Lacy's case, three CEIC members concluded that a relationship between the vaccinations and her death was "possible," while two members thought that a relationship was "probable," the DoD said.

The two panels were used because of their "complementary expertise," the Pentagon said. The SVSWG has monitored adverse events reports about smallpox vaccination since the current vaccination program was launched in December 2002. The CEIC succeeds a committee that reviewed adverse events reported in the anthrax vaccination program between 1998 and 2001.

The SWSWG also reviewed three other cases in which vaccinated service members became ill or died, and the CEIC reviewed one of those cases. The panels found no association between the immunizations and those cases, DoD officials said. The diagnoses in those instances were drug overdose, pulmonary embolism, and atrial fibrillation.

Lacy was treated for her illness at a clinic at Fort McCoy and at nearby hospitals starting in mid-March, according to a DoD statement released this afternoon. Specialists who later treated her at the Mayo Clinic consulted with DoD clinical experts, the Minnesota Department of Health, and the CDC. After her death, the CDC and DoD conducted additional laboratory tests to investigate what happened.

Her death certificate lists the cause of death as "diffuse alveolar damage," the DoD said. The certificate also states that she had pericarditis (inflammation of the lining of the heart), a condition that has been seen in a number of military and civilian smallpox vaccinees this year. A DoD smallpox safety report issued in October said that 58 vaccinees had myocarditis or pericarditis after vaccination. But the CEIC found that Lacy's pericarditis differed from other myopericarditis cases seen after vaccination. "The CEIC noted that pericarditis developed late in this soldier's case and did not seem to be the main reason for her illness," the DoD said.

The department also said Lacy did not have meningitis, encephalitis, or evidence of vaccinia virus (the virus used in the smallpox vaccine) in her spinal fluid.

The statement noted that the smallpox and measles-mumps-rubella vaccines contain live viruses, while the other vaccines Lacy received were inactivated vaccines. But no evidence pointed to any one vaccine. "Live virus vaccines have traditionally been considered more vigorous in the spectrum of adverse events that can follow vaccination, but there is no objective data to affirm this in the case at hand," the statement said.

Systemic lupus erythematosus (SLE) is considered an autoimmune disorder. The DoD said the medical literature includes a few case reports of autoimmune disease occurring after vaccination, but there is no proof of a cause-and-effect relationship.

One key finding that implicated the immunizations in Lacy's case was "an unusual pattern of antibodies called anti-Ro antibodies that have been associated with lupus [SLE] in some patients," DoD reported. "A very small proportion of people who carry the antibody may experience some kind of 'trigger' that sets in motion a lupus reaction. This lab finding leads some to conclude that the vaccines may have triggered her lupus." However, Lacy had received multiple vaccinations previously, when she entered the military and earlier in life as well.

Because Lacy had been healthy, had been medically cleared for the vaccinations, and had provided all requested information during screening, "Neither DoD nor the soldier knew any reason not to vaccinate her," officials said.

Conditions and treatments that cause immune system deficiencies are listed as contraindications to smallpox vaccination in the absence of an actual smallpox outbreak. Since SLE is considered an autoimmune disorder, smallpox vaccination would be considered risky for people with the condition. (See vaccine information in CIDRAP overview of smallpox.) However, Lacy was not known to have the disease.

See also:

DoD Nov 19 news release
http://www.defense.gov/releases/release.aspx?releaseid=5799

DoD smallpox vaccine safety summary
http://www.smallpox.army.mil/event/SPSafetySum.asp

DoD Anthrax Vaccine Immunization Program site
http://www.anthrax.osd.mil/

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