January 8, 2014 | 2
I spent a year filtering spit and nasal washings, growing influenza in tissue cultures in a minimalist lab, and trying to develop an oral flu vaccine, all as part of my Infectious Diseases fellowship thirty years ago. We’re still not there…but for now, here is information to help you this year.
Every year, the strains of flu circulating change—that’s part of why it is so difficult to develop treatments for. Each of the strains is named for two surface proteins: H, or hemagglutinin, which helps the virus attach to cells, and N, or neuraminidase, which then helps it enter the cell. The numbers reflect variations in these surface antigens, resulting in somewhat different strains. This year’s major circulating strain is H1N1, which was called “swine flu” and resulted in the pandemic (worldwide outbreak) in 2009. David McCandless has a great visualization illustrating the overlap between major flu strains and the overlap between human and animal strains.
What do you need to know to survive this year’s flu?
It’s not too late. It takes about two weeks for immunity to the vaccine to fully develop.
Influenza kills. One of the scariest things about the H1N1 is that it has been particularly hard-hitting on healthy young adults and pregnant women, rather than the very young or elderly, who generally have higher death rates. This is why vaccination is recommended for all now, even if you are healthy.
The flu vaccine is safe, even in pregnancy—the flu shot vaccine that is generally given contains killed virus. In fact, it is even more important for pregnant women to be vaccinated, as they have a high risk of death.
The single-dose vaccines do not contain mercury; multi-dose vials do. Nor does it cause the flu. It can’t; the trivalent shot isn’t a live vaccine. Nothing we do carries zero risk, but any tiny potential risk is far outweighed by the risk of the illness.
What vaccines are available?
Because of mutations, the flu virus changes a bit most years. It is tough to try and predict what strains will be circulating. Surveillance is done world-wide to detect specific strains and help guide each year’s vaccine production, but the decision about what vaccine to produce must be made about half a year in advance, so choosing the right flus to include is a bit of a roll of the dice. Usually, the vaccine given is trivalent, made from three inactivated viral strains. This year’s vaccine has:
• an A/California/7/2009 (H1N1) like the pandemic 2009 virus;
• an A(H3N2) virus
• a B/Massachusetts/2/2012-like virus.
This year, there are other vaccine options available to many. A higher dose trivalent vaccine is available for the elderly, in hopes of boosting a stronger immune response. There are quadrivalent vaccines, which contain two influenza B strains as well as two influenza A strains (Fluarix, Fluzone, and Flulaval). Flumist is different, in that it is a live attenuated vaccine, meaning it is made from weakened (but still live) strains of virus, and is given intranasally. It can be used for healthy people, age 2-49, but not in pregnancy or for others who may be immunocompromised.
Egg allergies are no longer an excuse. Flucelvax is grown in tissue culture but contains miniscule amounts of egg protein (“total egg protein is estimated to be less than 50 femtograms (5×10-14 grams or 5×10-8 µg) total egg protein”).
Further advice on egg allergies are given here.
Last year, the FDA approved Flublok, a recombinant influenza vaccine. This is interesting, in that it is not made from whole virus particles, but just from the surface protein hemagglutinin, which is important in stimulating the immune response. There are no eggs used in production, so allergies are not an issue, and production is speedier than with traditional systems. Flublok is produced by altering an insect virus called baculovirus to produce hemagglutinen. Insect cells are then infected with this virus, harnessing it to manufacture the hemagglutinen, which is then harvested for vaccine. While large quantities of the protein can be made for vaccination, thus far the vaccine has been only ~45% effective.
It is critical to develop non-egg based vaccines because the traditional production method—growing the virus in eggs—is very labor and time intensive. Once a new strain of flu is identified, the World Health Organization (WHO) estimates it would take 4-5 months to produce a vaccine in response. WHO and the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) further estimate “It would take 4 years to produce enough vaccine to meet total global demand” in the case of a pandemic. And because production only occurs in a few countries, this would result in huge disparities in the availability of vaccine.
The level of protection offered by flu vaccine varies from year to year. A Cochrane review showed efficacy of 73% when there was a good match between the vaccine and circulating strains of virus, but only 44% when there was not a good match. Others have estimated significant reduction in illnesses and hospitalizations. One study of elderly, for example, showed a significant reduction in hospitalization and death among those vaccinated. Observational studies are used to measure efficacy in large populations, comparing outcomes of people who were vaccinated to those who were not.
This year’s vaccine is estimated to have a 50-60% efficacy.
It’s a bit hard to interpret efficacy data. For example, is efficacy a serologic (antibody) response, or surrogate (a marker) endpoint, or is it preventing actual illness? Is a diagnosis of “the flu” based on the clinical symptom constellation, or does it require lab diagnosis? If lab, is that based on a rapid antigen test, which has a relatively low sensitivity (62%), or a PCR test or culture, both of which are more accurate but not readily available outside of major hospital centers?
As an Infectious Disease physician, I tend to come down on the pro-vaccination side for all vaccines, wanting to protect my patients and family. I believe that is our ethical responsibility as health care workers.
Major professional societies support mandated vaccines as a necessary public health initiative. Clearly, mandates for anything will have opposition, as noted here and here. Some hospitals are requiring masks for those who refuse; others increasingly make vaccination a condition of employment. There is an irony, however, in that some hospitals penalize employees who call off sick, even when staffing would not be severely disrupted.
How to limit illness spread
Keep your distance from those who are ill. Wash your hands or use hand sanitizer. Keep your hands away from your face—people often inoculate (infect) themselves with infection that way. Encourage those who are ill to deposit tissues directly into a bag and then use hand sanitizer before resuming other activities.
When to call or go to the doctor
I recommend the following to my patients: In general, if you are healthy, flu is generally miserable but self-limited. On the other hand, if you have chronic medical illnesses, are elderly, pregnant, obese, or are a young child (<5), more caution is generally warranted and seeking care should be done promptly. This year is a bit different, as H1N1 seems to be striking young adults particularly virulently, as it did disturbingly in 2009.
Signs of more serious illness include shortness of breath, pain with breathing, lethargy, and dehydration. If you experience any of these symptoms or if you initially improve and then get much sicker, you should seek care promptly, as pneumonia is a common and serious complication of influenza.
Medications to reduce the discomfort from a high fever include Ibuprofen (Advil or Motrin) and acetominophen (Tylenol or Paracetamol). Remember that children and teens should not be given aspirin, as this may cause Reye’s syndrome. Also be certain not to exceed the recommended daily dosages for ibuprofen and acetaminophen. (Overdoses of Tylenol can be deadly).
If in any doubt, call your doctor or go get checked.
There aren’t many options for specific antiviral treatment.
The two older drugs, amantadine and rimantadine were effective for influenza A (but not for B). Unfortunately, resistance has developed to this class of drugs by both H3N2 influenza and by H1N1, so they are no longer useful.
Another class of drugs are neuraminidase inhibitors, which include Zanamivir (Relenza) and oseltamivir (Tamiflu). Unfortunately, these are effective only if given within the first 48 hours of illness and, even then, have only been shown to reduce illness by 1 day. Despite lukewarm data, the CDC seems to be surprisingly enthusiastic about antiviral use. In general, treatment is recommended only for high-risk individuals or those who are hospitalized. Frankly, in patients who are sicker, we often are less concerned about good data than trying anything plausible…
Others are far more critical of data on Tamiflu. For example, Ben Goldacre, physican and author of Bad Science, has long been vocal in his concerns about the drug. And earlier this year, Trish Groves, deputy editor of British Medical Journal, wrote a pointed editorial summarizing concerns about the drug.
The BMJ’s open data campaign report on Tamiflu concluded:
“• WHO recommends Tamiflu, but has not vetted the Tamiflu data.
• EMA approved Tamiflu, but did not review the full Tamiflu dataset.
• CDC and ECDC encourage the use and stockpiling of Tamiflu, but did not vet the Tamiflu data.
• The majority of Roche’s Phase III treatment trials remain unpublished over a decade after completion.
• In Dec 2009, Roche publicly promised independent scientists access to ‘full study reports’ for selected Tamiflu trials, but to date the company has not made even one full report available.” [Roche released all data to Cochrane reviewers in 2013].
The bottom line? If you haven’t been vaccinated against flu yet this year, do so. The flu is spreading. If you do become ill with flu-like symptoms, be certain to stay well-hydrated, and if you exhibit any of the symptoms I mentioned earlier, call your doctor sooner rather than later. Flu is nothing to sneeze at…I’ll have more on medications for influenza in an upcoming post.
“Molecules to Medicine” banner © Michelle Banks
Plaque assay – Y Tambe, Wikimedia
Flu structure – NIH via Wikipedia
Influ-venn-za image – David McCandless
Inoculating eggs with seed virus image – Vincent Moncorgé, Sanofi Pasteur
Tissue culture cells – Alcibiades, Wikipedia
Syringe filter image courtesy Qorpak