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The Recent Flu Vaccine Crisis: A Review

By: Dr. F. Edward Yazbak

The flu vaccine manufactured by Chiron in its British plant was banned for use in the United States. The CDC mounted an intense publicity campaign in the fall of 2004 because of the resulting "perceived" shortage.

The "threatening" epidemic never materialized and the flu season will be ending soon.

The following are the lessons to be learned from this season's happenings:

  • Hype and propaganda may or may not result in better vaccination rates
  • The three virus strains in next year's flu vaccine may not be the predominat ones
  • Influenza A virus will become increasingly resistant to anti-viral medications
  • Avoiding exposure remains the ideal prophylaxis
  • Selective vaccination should be closely monitored
  • Chicken soup, Vitamin C, liquids and rest remain safe and effective therapies.

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Last fall, the poor old folks of Florida had not recovered from back to back hurricanes, in the worst season in a quarter century, when they were thrust into another alarming situation.

The flu vaccine manufactured in a British plant was contaminated with Serratia Marcescensand its importation into the United States was banned.  As a result, the Country was faced with a "shortage" of 50 million doses of vaccine. The fate of a million doses from the same plant that had already been shipped to the US in July    - before the ban- remains unknown.

Maybe like the MMR in Vive La Difference (1), they found their way to South America.

Maybe they didn't.

Starting in October, the CDC promulgated serial recommendations and priority lists. There were frequent Press releases and warning bulletins that further frayed the nerves of people of all ages and particularly the elderly, not only in the Sunshine State but also in the other forty nine. 

The News Outlets reported the "crisis" around the clock and had their own "experts" for interviews and advice. Long lines half-way around the block, formed everywhere. In the warm south, the poor old people stood in shorts in the scorching sun, with their straw hats and water bottles. In the north, the elderly bundled up in scarves and overcoats, because of an unusually cold fall and stood shivering and waiting.

Those who "got the shot" went home very happy just as if they had just won at Bingo. The others went home tired and disappointed but vowing to find another line and another building the following day.

There were even rumors that a lottery system may be used for fair distribution of the vaccine that was in such very short supply.

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The first death of the flu season was recorded in California.

On October 13, a 79-year old lady in Lafayette collapsed after standing in line for four hours, in the heat, outside a supermarket. She hit her head and died the following day.

In nearby Concord, another East Bay community, two women ages 76 and 83, were hospitalized a couple of days later, also after collapsing from heat exhaustion while patiently waiting in another long slow line, this time outside a discount store. (2)

As expected, the shortage brought out the worst in people. Some drug distribution companies were charged with price gouging and in some places, $85 vials of flu vaccine were going for $700. (3)

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The panic remained carefully and relentlessly orchestrated although very few cases of flu or "Influenza like Illness" (ILI) were being reported.

In fact as of mid - November, twenty-three states had not yet had a single case of laboratory-confirmed influenza and there had only been 170 such cases in the rest of the Country, an average of one laboratory-documented case of influenza for every 1.7 million Americans. (4)

On November 3, 2004, in spite of the slow start of the flu season, the CDC published its Interim Chemoprophylaxis and Treatment Guidelines for the 2004-2005 Season, encouraging the use of amantadine or rimantadine for chemoprophylaxisand oseltamivir or zanamivir for treatment of Influenza "as supplies allow".

People at "High Risk" were to have priority in case of shortage. Details about both treatment and prophylaxis with the antiviral medications were carefully outlined. (5)

The document also made reference to the Strategic National Stockpile and offered reassurance that "Efforts are underway by Health and Human Services to procure additional supplies of antiviral medications. Some of the supply will be held in reserve in the event of influenza pandemic. However, some of the supply will be made available to States and Territories for use inoutbreak settings, as might occur in a hospital or long term care facility".

In a separate document, (6) the CDC listed the side effects of the four recommended antiviral drugs and warned about drug interactions. Noteworthy was the statement about their use during pregnancy: "No clinical studies have been conducted regarding the safety or efficacy of amantadine, rimantadine, zanamivir, or oseltamivir for pregnant women; only two cases of amantadine use for severe influenza illness during the third trimester have been reported. However, both amantadine and rimantadine have been demonstrated in animal studies to be teratogenic and embryotoxic when administered at substantially high doses. Because of the unknown effects of influenza antiviral drugs on pregnant women and their fetuses, these four drugs should be used during pregnancy only if the potential benefit justifies the potential risk to the embryo or fetus (see manufacturers' package inserts)."

For the sake of brevity, only reactions (7) occurring after Amantadine, will be listed. Amantadine is only effective against Influenza Aand is only used to "prevent" thedisease. It is therefore not intended for treatment. (Amantadine is also used in the treatment of Parkinson's disease and drug-induced extra-pyramidal reactions ) .

The adverse reactions reported in up to 10% of patients taking the recommended dose of amantadine are dizziness, insomnia and nausea.

Up to 5% of the patients on the medication complained of or exhibited agitation, anxiety, confusion, depression, diarrhea, dry mouth, dry nose, hallucinations, headache, hypotension, irritability, fatigue, loss of appetite, nervousness and peripheral edema.

Less than 1% of patients reported: congestive heart failure, difficulty breathing, eye/optic nerve pathology with vision problems, hyperkinesia, hypertension, psychiatric difficulties, skin rashes, slurred speech, urinary retention etc

Convulsions and suicidal tendencies /suicide were very rarely reported (<1:1000).

It should be noted that a study describing resistance of the Influenza type A virus to Oseltamivir, (8) one of the two drugs recommended for treatment, was published in The Lancet in 2004.

According to the authors, some children were still infectious after five days of treatment and some 18% of the treated children developed mutant drug-resistant viruses as early as four days after therapy with Oseltamivir was initiated.    

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Vaccine and antiviral drug manufacturers were not the only industries hoping to cash in on this year's "crisis". Makers of antibiotics were also getting ready to have their piece of the pie "¦and eat it too.

The division vice president of investor relations of a leading pharmaceutical company told analysts that the shortage of flu vaccine could provide "some incremental positive impact." The reason was that the sales of broad-spectrum antibiotics are affected by the severity of the flu season as those antibiotics are used to treat secondary infections and complications such as pneumonia and bronchitis. The analysts were reassured that as the severity of the flu season "ramps up", secondary infections will increase and the demand for the company's main broad-spectrum antibiotic, and its sales, will also increase.

During the fourth quarter of 2003 that included much of last year's flu season, the broad-spectrum antibiotic in question generated $225 million in US sales, a 21.4 percent increase over the fourth quarter of 2002. (9)

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The vaccine "shortage" resulted in unique situations and events.

In early December, a licensed practical nurse in scrubs calmly walked into a hall at a college in Minneapolis and administered "flu shots" to students over three consecutive days.

At least 38 students were vaccinated and each was charged $20 for the injection. (10)
 

It was later revealed that this nurse worked for a healthcare service that held flu vaccination clinics nationwide. Her supervisors had apparently asked her to dispose of partially used vials of vaccine rather than return them to the company headquarters in Maryland. According to her lawyer, she decided instead to sell the available vaccine to raise money for the American Heart Association.

Apparently this lady's daughter attended a school that was conducting a contest and awarding stuffed animals to the students who raised the most money for the Heart Association. The lawyer added that indeed all proceeds from the vaccination sessions had been turned over to the daughter's gym teacher.

The American Heart Association immediately denied any involvement or even knowledge of the incident and the local Health Department reassured the vaccinees and their parents that the used vaccine appeared legitimate.

The College apologized to the students, reviewed the existing security measures and released a new recommendation: In the future, all vendors will have to display their permits. The students accepted and appreciated the apologies

Just as strange an event took place on the East Coast.

According to the Associated Press, a 37-year old NJconvenience store ownerwas arrested on December 6 and charged with smuggling flu vaccine into the country. Apparently he had contacted a local hospital earlier offering 5,000 doses of vaccine for sale at $55 a dose. (11)

The hospital administration promptly notified the Federal authorities which investigated the case and seized the vaccine.

Apparently even the agent in charge of the federal Immigration and Customs Enforcement agency's Newark office appeared surprised at the audacity of the plan.

The U.S. Department of Homeland Security also became involved and conducted its own investigation. A spokesperson later reassured everyone and declared that the illicit flu vaccine shipment "did not get into the nation's flu vaccine supply".

Just a week earlier, New Jersey had reported its first case of influenza.

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In early December, U.S. health officials approved the importation of up to 4 million doses of influenza vaccine made by GlaxoSmithKline (GSK) thus bringing the total to 65 million doses of vaccine for the current season. (12)

Because it had not been approved by the FDA and because of the "crisis situation", Fluarix, the Glaxo vaccine, was approved as an "investigational drug". On December 6, the CDC Director told an AMA briefing session "since these vaccines are investigational they will require informed consent." When questioned further, the Director added that "a standard medical consent will be required."

Health and Human Services Secretary Tommy Thompson was pleased with the Glaxo deal and reassured the Nation by stating "With the latest purchase we will be able to protect more high-risk Americans this flu season in communities across the country".

The following day, N J Burkett, of ABC "“ Eye Witness News-New York (13) reported:

"Strange Turn in Flu Shot Shortage: City Has a Surplus;
Concern about High Risk Patients Rises, as Clinics Sit Empty".

On December 10, NBC News-San Diego reported that there was now plenty of flu vaccine in that city and that one clinic had over 18,000 doses of pediatric flu vaccine and no takers. A spokesman for the clinic was quoted as saying: "We have a quarter million dollars in vaccine sitting in the refrigerator that we won't be able to use by the end of flu season "¦We've seen the war zone of about 6,000 people a day trickle down to about 50 people a day." (14)

On December 13, CNN informed its national audience that there was now a surplus of vaccine in many areas and that long waiting lines had disappeared.

At a Seattle grocery store that week, the line in the express checkout lane was longer than the line to get flu shots.

A spokesman for the Texas Department of State Health Services describing the situation said "It's one of those things like Beanie Babies or something"¦if you can't get something you've got more people wanting them". (This fellow was right. I remember a trip to London: when instead of sightseeing we went shopping for Beanie babies. I also recall a fellow pediatrician driving to Canada, in a winter storm, just before Christmas, to grab a Cabbage Patch doll for his niece. )

Public health officials said that they were hoping that the demand was dwindling because "the people who need flu vaccine the most: babies, the aged and the infirm had been vaccinated". But they also frankly acknowledged that frustration and apathy might also be factors"¦"Being told they can't get a desired immunization is an unfamiliar and unwelcome sensation for most Americans."

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The CDC has recently recommended vaccination of infants older than six months and children. The CDC recommendation for babies under age 2 was apparently partially based on a CDC-funded retrospective study of some 30,000 children enrolled in a Colorado health plan. The enrolled children were not randomly assigned to receive the flu vaccine or a placebo and the study results were reported in the CDC on-line MMWR (Morbidity & Mortality Weekly Report), but not published in any peer-reviewed publication. When asked whether the flu vaccine caused any adverse reactions, the lead investigator stated that "Hospital admissions were not tracked, and the parents were not interviewed". (15)

Before the flu vaccine became recommended for all children older than 6 months, it was usually administered to children with chronic illnesses and especially recommended for those with asthma (Reactive Airway Disease) to protect from the viral illness itself and its complications.

A recently published study (August 2004) from Strong Children's Research Center in Rochester, compared outcomes in vaccinated and unvaccinated children, as regards to their asthma symptoms and complications. The results were surprising and deserve attention. After adjusting for other variables, the vaccine group had a significantly increased risk of asthma related clinic visits and ED visits (odds ratios 3.4 and 1.9, respectively).

The authors concluded "This study failed to provide evidence that the influenza vaccine prevents pediatric asthma exacerbations".  (16)

Though understated, such conclusion is significant.

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The Mortality and Morbidity Weekly Report: (December 17: 2004 / Vol. 53 / No. 49 )

Only the "Estimated Influenza Vaccination Coverage among Adults and Children --- United States, September 1--November 30, 2004" is reviewed. (17)

To assess the use of influenza vaccine and the primary reasons reported for not receiving vaccine, questions were added to the ongoing Behavioral Risk Factor Surveillance System (BRFSS) survey.

The following information is based on data collected between December 1 and 11 on self-reported vaccination during the period September 1 to November 30, 2004.

The analyses were based on 16,713 interviews conducted in 48 states and the District of Columbia. Data for Nevada and New Mexico were not available. The median response rate for states/areas for the preceding month (November 2004) was 52.3% (range: 23.2%--76.8%). For 2003, the last year for which yearly response rates are available, the median response rate for states/areas was 53.2% (range: 34.4%--80.5%). Estimates were adjusted to account for differential probabilities in the sample selection, the age- and sex-specific population from the 2003 census for each state, and the size of the state population. Statistical analysis software was used to account for the complex sampling design and to calculate standard errors and confidence intervals.

Among adults in all priority groups, 34.8% reported receiving an influenza vaccination during between September 1 and November 30. Coverage was highest (51.1%) among persons aged >65 years, followed by health-care workers with patient contact (34.2%) and high risk adults (19.3%). The percentage of persons reporting that they obtained an influenza vaccination during this period was smaller in each of these groups than the percentage that said they obtained a vaccination during the previous influenza season, September 1, 2003 to March 31, 2004.

Among persons aged >65 years who reported receiving influenza vaccine during the 2003-04 influenza season, 71.7% reported also being vaccinated during the 2004--05 influenza season. Among adults in priority groups who had not yet received influenza vaccine, 23.3% reported that they attempted to obtain vaccination but could not; among persons aged >65 years, the proportion was 32.5%. Among adults in priority groups, 10.0% of adults said they were saving the vaccine for others, and 6.5% thought that they were not eligible to receive the vaccine.

36.6% of children aged 6-23 months and 26.8% of children aged 2-17 years with high-risk conditions were vaccinated. 51.6% of children with high-risk conditions aged 2-17 years who were vaccinated during the 2003-04 influenza season received the vaccine this year. 

62.9% of respondents with an unvaccinated child aged 6-23 months said that they believed that the vaccine was not needed. 8.4% reported that they tried but could not obtain any vaccine. 38.4% of respondents with an unvaccinated child aged 2-17 years with a high-risk condition reported that they thought vaccination was not needed and 14.4% reported that they tried but could not secure a vaccination.

So, by the end of November2004 and in spite of major efforts and intense publicity 

  • Almost two thirds of the adults in the priority group had not been vaccinated
  • Also not vaccinated were almost half of the elderly, two thirds of the health-care workers and 80% of the "high risk" adults. 
  • Fewer adults in all groups had received the flu vaccine when compared to 2003
  • Over 70% of children at high risk had not been vaccinated 
  • Only half of the high-risk children vaccinated during the 2003-04 season had been revaccinated
  • Over 60% of parents of unvaccinated infants and toddlers believed that the vaccine was needed
  • Almost 40% of parents of unvaccinated older children in the "high risk" category remained unconvinced that vaccination against the flu was needed. 

The (unidentified) Editor of the report did not seem concerned with the results.

Seeing the glass half-full, he/she commented: 

  1. Because of the survey limitations, the results were probably better than they appeared
  2. Persons in the priority groups are receiving vaccine at higher rates than those in non-priority groups
  3. Because vaccine coverage is below par, efforts should continue "as vaccine becomes available
  4. Because (62.6%) of respondents with unvaccinated 6-23 month-old children did not think vaccination was needed, further efforts are needed to educate the public about the new influenza vaccination recommendation for young children.
  5. The 36.6% vaccination rate among 6-23 month-old children is still better than last year's rate of 7.4%.                                                                                             

Note: It was only in April 2004 that the Advisory Committee on Immunization Practices recommended the vaccination of 6 to 23 months-old children.

The Latest Statistics

During the period of January 23-29, 2005,the WHO and NREVSS laboratories in the United States reported testing 2,986 specimens for influenza viruses, of which 474 (15.9%) were positive.

Since October 3, the two laboratories have tested a total of 58,314 specimens for influenza viruses and 5,138 (8.8%) were positive. Of these, 85.8% were influenza A viruses. 29.2% of the influenza A viruses were further sub-typed and 99.6% of them were influenza A (H3N2).

The Pediatric Population

The number of Laboratory-confirmed influenza associated pediatric hospitalizations during October 3, 2004"“January 22, 2005 was lower than in prior years

There were four pediatric deaths reported to CDC: this year. No details are available. In the past, many of the children who died had underlying serious conditions

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The latest news

It was just revealed (San Francisco Chronicle, February 9, 2005 ) that a new strain of ]Influenza A virus, dubbed A/California/7/2004, made a rapid emergence in the western states and could cause a surge in the number of cases in the last two months of the flu season. According to the CDC, the new A/California strain, first cultured in Santa Clara now accounts for 20 percent of the Influenza A viruses tested. (18)

We obviously all recall that last year's vaccine (2003-2004) also did not contain the strain that prevailed during the outbreak.

On February 10, 2005, a panel of influenza experts met at the World Health Organization headquarters in Geneva and recommended inclusion of the California strain (A/California/7/2004(H3N2) in next season's vaccine. The US health authorities tend to follow the panel's recommendations.

The panel usually meets twice a year to formulate vaccines for the two hemispheres.

In a telephone interview, the WHO top influenza expert said that the panel has been wrong only once in the last 10 years. (19).

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Discussion

In the past, annual flu vaccination was advised for high risk individuals and health workers, a population of about 185 million people. In spite of the severity of the 2003-2004 flu season less than half that number was actually vaccinated (around 83 millions).

In February 2004, it was revealed that the CDC was considering Universal Flu Vaccination". The recommendation to vaccinate all Americans every year "would improve overall vaccination rates, boost vaccine supply and prepare the public health system for mass vaccinations if a flu pandemic strikes". (20

The CDC has spent much time, effort and money this fall on what was called the "flu vaccine crisis".

In retrospect and with 20/20 hindsight, it is likely that there was enough flu vaccine available for those who needed and wanted it.

In the spring of 2004, the CDC had decided that just about everyone older than six month should receive the flu vaccine even those who had "never needed" the vaccine in the past. 

When the problems with Chiron surfaced and it became clear that the available vaccine supply would not be enough for everyone, the CDC recommended that healthy children and adults forgo the vaccination so that those individuals "who really needed it", the elderly and those at high risk, could get it.

When a large surplus of vaccine remained on refrigerator shelves, the CDC changed its recommendation again and offered the vaccine to anyone who "wanted" it.

The promised epidemic never came and there is every indication that hopefully, the 2004-2005 flu season will end up being one of the mildest.

Parting Questions.

  1. Is the flu vaccine as effective as the CDC suggests?
  2. Is it as safe as it can be?
  3. Is the vaccine really needed for healthy adults, infants and children?
  4. Is it really safe for pregnant women?
  5. Why are recommendations different in other Western Countries?

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References

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  8. Kiso M, Mitamura K, et al. Resistant influenza A viruses in children treated with oseltamivir: descriptive study. Lancet.2004;364:759-765].
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  16. Christy C, Aligne CA, Auinger P, Pulcino T, Weitzman M. Effectiveness of influenza vaccine for the  prevention of asthma exacerbations.  Arch Dis Child. 2004Aug;89(8):734-5. PMID: 15269071
  17. MMWR December 17, 2004 / 53(49);1147-1153
  18. link
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