Swine Flu has brought an awareness of the catastrophic potential inherent in pandemic influenza to the public consciousness and led many to panic. Industry has long played a major role in protecting us against epidemic influenza, providing doctors and patients with vaccinations and medications to help protect and treat the weakest individuals in our society: the young and old. However, pandemic flu frequently kills the healthiest in society; a hallmark of the 1918 Swine Flu Pandemic that left 500,000 dead in the U.S., far more that the average of 36,000 dead in a typical year.
This week, I had a discussion with Bill Enright, President and CEO of Vaxin Inc., about their efforts to create a vaccine for pandemic Flu. Our daughters are kindergarten classmates and over the last two years I have enjoyed the opportunity our friendship has afforded me to learn about the vaccine industry. As “Swine Flu” began to dominate the headlines I asked him to participate in a dialogue with me believing that a discussion between a clinical physician and a vaccine scientist would be interesting and informative for a reader without giving in to hysteria. He was kind enough to give of his own time and a part of the discussion follows:
STEVE: What is Vaxin, Inc.?
BILL:. Vaxin is a vaccine development company focused on needle-free vaccines to protect against influenza (both seasonal and avian influenza) and anthrax. Using technology developed at the University of Alabama at Birmingham, by our scientific founder Dr. De-chu Tang, we have been able to show proof of principle with our platform, intranasal seasonal influenza vaccine, and have just completed enrollment in a Phase I clinical study with an intranasal pre-pandemic influenza vaccine. We are also investigating patch-based vaccines.
STEVE: What is the difference between the vaccine you are developing for Pandemic Influenza and the vaccine given yearly for Epidemic Influenza?
BILL: Epidemic, or seasonal, vaccines are trivalent vaccines composed of three influenza strains (two A and one B) anticipated to be circulating. The CDC and the WHO spend considerable effort in monitoring the circulating strains around the world before making a decision on which strains should be included in that year’s vaccine. However, several changes could occur which result in the vaccine not being a good match for a particular year: mutations could change a strain, new strains could evolve or different strains than anticipated could predominate.
Pandemic vaccines will be made to the circulating influenza virus causing the pandemic. Vaccines made in advance of a pandemic are really “pre-pandemic” vaccines as they are attempting to estimate which influenza strain may make the jump to a pandemic and enable stockpiling and/or vaccination of at-risk individuals with the belief that the vaccine will mitigate symptoms and decrease mortality through cross-strain protection while a true pandemic vaccine is being developed/manufactured.
STEVE: How long does it take to produce an epidemic trivalent vaccine and is it feasible to have the current H1N1 strain or “swine flu,” included in the standard flu shot this fall?
BILL: That is a complex question. Do you include it as a 4th component? Replace one of the other A strains? Provide it as a separate vaccine? Manufacturers are currently trying to assess how much and of which type of vaccine they would be able to provide given a limited egg supply (since vaccine components require incubation in chicken eggs). Chicken populations take a significant amount of time to increase to add egg capacity. Seasonal vaccine antigen doses are typically 15µg and it takes approximately 1 egg for one, 15µg dose. To date it has taken 90µg of antigen to show similar levelsof efficacy for pandemic vaccines. Therefore, whether or not there is a sufficient egg supply and how that may impact the traditional epidemic vaccine is being discussed and calculated as we speak.
The length of time it takes to manufacture the epidemic trivalent vaccine depends a lot on the specific strains and how different the vaccine is from the previous year. For instance, the 09/10 vaccine will contain 2 of the same strains as the 08/09 version, only the B strain is different. The CDC put forward this years policy document on February 25th, identifying which exact strains were to be included in this year’s vaccine. Many manufacturers had already started the production efforts on the seed strains guessing that these would be the strains based on available surveillance of circulating strains. Typically the total process begins in December or January for most manufacturers. Usually the first vaccines are ready to ship to distributors in August or September. In certain years the process can take longer than usual because not all strains of influenza grow well in chicken eggs, including the recent H1N1 virus. New “reverse genetic” techniques are helping to alleviate this problem but the rate of growth and yield of virus continues to be a concern to manufacturers.
STEVE: Do you have any ongoing clinical trials for the H5 pre-pandemic flu?
BILL: Vaxin is currently completing a Phase I clinical trial for an intranasally delivered vaccine against the H5N1 influenza virus. This is the first step in getting a vaccine approved for use by the FDA. Typically Phase I trials involve a small number of otherwise healthy volunteers that agree to be vaccinated to allow us to test and ensure that our vaccine does not cause any serious unwanted safety concerns. Vaxin’s study involved 48 people that were divided into 3 groups of 16. Each group of 16 received a different dose of the vaccine on the first day and then received a second administration of a second dose 28 days later. Within each group of 16, only 12 people actually receive the vaccine and 4 people receive a placebo. Until the end of the study, no one knows who received the vaccine and who received the placebo.
STEVE: The mortality rates for H5 influenza have been between 30% and 70%. Did this lead you to choose H5 as a focus for your pre-pandemic vaccine?
BILL: The focus on H5 as a target for pre-pandemic vaccines is a result of the high degree of mortality seen in those that have been infected with the virus. While the 1918 flu had a catastrophic impact on the world and a large loss of life, it is estimated that the mortality rate was about 2%. However, it was able to spread very rapidly. Similarly, other pandemics from H2 and H3 outbreaks had relatively low mortality rates (estimated to be between 0.1%-0.5% for both the 1957 and 1968 pandemics).
STEVE: Can you speak about the delivery system you are using to deliver this vaccine?
BILL: Vaxin’s technology includes the use of another virus called adenovirus. This is a virus commonly found in nature which typically causes mild respiratory illnesses or cold like symptoms. It has a natural ability to infect humans at a very high rate. We have modified this virus so that it can no longer reproduce and we have incorporated a very small piece of the flu virus into the adenovirus. The adenovirus then infects people like normal but instead of making more adenovirus, it makes a piece of the flu virus. The body sees this in the same way it sees the flu…as a bad foreign protein and jump starts the immune system to get rid of it. In addition, our vaccine is given intranasally, the same way that the body normally sees both adenovirus and the flu. We believe the body responds in a very similar fashion in identifying and clearing the potential threat.
STEVE: Too many suffered complications to the H1N1 Swine Flu vaccine rushed through production in 1976; this leads me to ask if any corners would need to be cut, in terms of patient safety, to get a swine flu vaccine ready in time this year?
BILL: I am not familiar enough with the issues associated with moving the 1976 swine flu vaccine through the process to know about shortcuts taken, but the issues identified may still be issues. The result however was a significantly higher incidence of Guillain-Barre Syndrome (GBS) in those vaccinated vs those unvaccinated; 13.3 vs 2.6 per millions of people contracting Guillain-Barre, respectively. Note, significantly larger safety studies than are typically done for influenza vaccines would have been required to detect this event.
The current H1N1 swine flu vaccine would be against a very similar antigen and made with similar technologies for the most part and therefore the risk of GBS may still be prevalent. This will be weighed as a risk/benefit calculation when deciding how to proceed. It will depend in large part on the true mortality rate of the H1N1 swine flu vaccine. This was originally estimated at about 10%, but as identified cases of H1N1 and associated deaths are “confirmed” as opposed to being “probable” cases and the reporting becomes more accurate, it is now about 1% and falling. At 10% it is likely worth the calculated risk of GBS but at what point does the risk of death have a higher impact than the potential risk of GBS
STEVE: What percentage of health care workers, in our country, typically receive a flu shot?”
BILL: Only 36% of health care workers in the U.S. on average receive an influenza vaccine annually. (Source: CDC. Prevention and control of influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 2003; 52 (RR8): 1-44.) Therefore, with a disease that can be spread two or more days before a person is symptomatic, an individual healthcare worker has a tremendous opportunity to spread the disease, without knowing it, to a population that is likely very susceptible, those that are sick and immune compromised to begin with.
STEVE: Do you have any suggestions for my colleagues and friends who tell me they get the flu from a flu shot?
BILL: It is scientifically not feasible to get the flu from a flu shot unless the vaccine has not been made appropriately and tested adequately. The licensed influenza vaccines on the market today are primarily inactivated whole virus or split subunit vaccines. Essentially the flu virus is grown in chicken eggs, purified and inactivated by heat or chemicals. The virus is unable to replicate and therefore cannot cause the flu. Usual side effects from any vaccination, because of the stimulation of a robust immune response from the body, include symptoms that some people associate with the flu, e.g., fever, body aches, sniffles etc. These symptoms are typical of many vaccinations including flu. Similarly in the new live virus vaccine (FluMist ®), the virus has been adapted to grow only in a cold environment. Once in the body its ability to replicate is severely limited and again not feasible to cause the flu.
All in all vaccines are the most cost effective medical procedure invented. Their use over the past century has saved millions of lives and untold expense with several previously common diseases now relatively under control or near complete eradication. Many people do not realize the annual cost, in lives lost, hospitalizations and subsequent economic costs, that influenza outbreaks inflict. Our ability to track and monitor influenza outbreaks and continual improvements in technologies and manufacturing processes are allowing us to attack influenza with the same vigor. While the world is more prepared than ever before to deal with potential pandemic influenza outbreaks, we still have room for improvement to ensure adequate, rapid access in all parts of the world. Vaxin is hopeful that our technologies and products will continue to advance this effort for rapidly available, safe, effective, easy to administer vaccines.