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Autumn Pandemic Vaccination: Go-Slow, Moderate Effort, or Full Throttle?
On August 26-27, 2009, the Centers for Disease Control and Prevention, in conjunction with
conducted an online “Public Engagement Dialogue on the H1N1 Vaccination Program.” I (M. O’Leary) learned about the opportunity to participate from an email sent by the International Association of Emergency Managers. A second WebDialogue is scheduled for a different group of volunteer participants August 31-September 1, 2009. The goal of the two-day WebDialogue, say its producers, “is to give the Centers for Disease Control and Prevention (CDC) input on its voluntary fall vaccination program against the 2009 H1N1 flu virus,” because the CDC is “considering the scope of the program for vaccinating Americans against the novel H1N1 pandemic influenza virus.” Seventy-nine people signed up to participate in the August 26-27, 2009 Web Dialogue.
The first topic I visited on August 26, 2009, was “Vaccination program approaches,” about which someone (expert panelists?) wrote the following introduction: Uncertainties remain and will remain about H1N1 influenza. For example, it is not known how widespread and severe H1N1 influenza will be in the US next fall or how much public demand there will be at the time for vaccine. Also, because of the complexities and resources required to plan for mass vaccination well in advance of the epidemic, these uncertainties and complexities pose a difficult dilemma. Should the US take a “full throttle” or a “go easy” approach to mass vaccination, or an approach somewhere in-between? Three vaccination program approaches have been identified….Each approach has pros and cons. A difficult choice must be made in advance. Scaling up or scaling down during an epidemic will be “too little too late” to protect people from getting ill, or “too much too late” so that limited resources are wasted during a period of economic hardship. The experts who participated in the discussion about the three vaccination approaches were:
The Web Dialogue-associated author of the following text is unknown: With the “go easy” approach a few extra sites for vaccination are planned. The goal is to meet an expected low public demand for vaccine and to do so throughout the flu season without rushing to vaccinate early on. Program activities in the areas of communication, volunteer involvement, partnerships, safety, disease, and coverage monitoring will be slightly increased over those undertaken during a regular flu season. Pros
*Provides the best opportunity to collect more information about the disease and the effectiveness and safety of the vaccine before vaccinating large numbers of people. Cons
*Will leave health programs and providers less ready to vaccinate if disease activity or severity increase significantly and public interest in vaccination suddenly increases as a result. The Web Dialogue-associated author of the following text is unknown: The goal of a “moderate effort” approach is to promote vaccination to eligible groups, set up extra vaccination sites beyond those used in a regular flu year, and to vaccinate relatively quickly a large number of the eligible groups. An aim of the program is to raise the expected low public demand for vaccine. Regular program activities are considerably enhanced to accomplish this especially in the area of communication, but other program areas such as volunteer involvement, partnerships, and program monitoring are also intensified. Pros
*Strikes a balance between doing too little or too much to prepare for novel H1N1 influenza when there is no way of knowing for sure how widespread or how severe the disease will be or exactly how effective or how safe the vaccine will be. Cons
*Approach does not accomplish as much preparation as would be desirable to respond appropriately with vaccination if disease activity and severity increase significantly, and would leave some people still vulnerable. The Web Dialogue-associated author of the following text is unknown: Significant additional federal, state, and local funds are invested in creating numerous extra vaccination sites in both the public and private sectors. The aim of a "full throttle" approach is to create and to respond fully and speedily to significant public demand for vaccination even if the severity of the illness is initially perceived to be low. Extensive communication activities are undertaken to stimulate public demand, and extensive networks of volunteers and partners are identified and ready to spring into action. Monitoring of the program activities is carried out aggressively to collect timely data and take any corrective actions needed to improve the ongoing program or to protect public safety. Pros
*Satisfies the need to feel safe rather than sorry no matter what happens to flu next fall. Cons
*Will require use of federal, state, and local resources which may not be available or easily found in this time of economic hardship and may compromise several other public services. Question 1: Can you explain why pregnant women are considered a high-risk category and are a priority for immunization? This seems counter to general advice on limiting the use of medicine while pregnant. Dr. Malinoski responded: In early May of 2009, the MMWR reported on cases of H1N1 in pregnancy, noting the following: On May 12, this report was posted as an MMWR Dispatch on the MMWR website (http://www.cdc.gov/mmwr). CDC first identified cases of respiratory infection with a novel influenza A (H1N1) virus in the United States on April 15 and 17, 2009 (1). During seasonal influenza epidemics and previous pandemics, pregnant women have been at increased risk for complications related to influenza infection (2-5). In addition, maternal influenza virus infection and accompanying hyperthermia place fetuses at risk for complications such as birth defects and preterm birth (6). As part of surveillance for infection with the novel influenza A (H1N1) virus, CDC initiated surveillance for pregnant women who were infected with the novel virus. As of May 10, a total of 20 cases of novel influenza A (H1N1) virus infection had been reported among pregnant women in the United States, including 15 confirmed cases and five probable cases.* Among the 13 women from seven states for whom data are available, the median age was 26 years (range: 15-39 years); three women were hospitalized, one of whom died. This report provides preliminary details of three cases of novel influenza A (H1N1) virus infection in pregnant women. Pregnant women with confirmed, probable, or suspected novel influenza A (H1N1) virus infection should receive antiviral treatment for 5 days. Oseltamivir is the preferred treatment for pregnant women, and the drug regimen should be initiated within 48 hours of symptom onset, if possible. Pregnant women who are in close contact with a person with confirmed, probable, or suspected novel influenza A (H1N1) infection should receive a 10-day course of chemoprophylaxis with zanamivir or oseltamivir. These data are consistent with a number of reports describing increased complications associated with seasonal influenza in pregnant women. According to the same report, The increased risk of complications is thought to be related to several physiologic changes that occur during pregnancy, including alterations in the cardiovascular, respiratory, and immune systems. Pregnant women with underlying medical conditions such as asthma are at particularly high risk for influenza-related complications. Because pregnant women are at increased risk for influenza complications, the Advisory Committee on Immunization Practices and the American College of Obstetricians and Gynecologists have recommended that women receive the trivalent inactivated influenza vaccine. Link is: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5818a3.htm Dr. Iskander responded, “Pregnant women appear to be at higher risk for severe complications from both seasonal and novel H1N1 influenza. ‘Killed’ vaccines such as the flu shot that do not contain live viruses are generally considered safe during pregnancy.” Question 2: Why were elderly excluded from prioritization for novel H1N1 vaccine? Dr. Malinoski responded: “At the July special ACIP [Advisory Committee on Immunization Practices (10)] meeting there were several reasons put forward to exclude elderly (over 64) from the target groups for immunization during the early days of the immunization campaign. The most compelling is that in spite of significant disease in other populations there have been no nursing home outbreaks of novel H1N1 disease. Related, only 1% of cases identified through 24 July 09 were in the over-64 population. In addition, people born before 1954 would have been exposed to H1N1 strains that may relate to the current novel H1N1. In an evaluation of antibody across age groups, less than 4% of individuals born after 1980 have pre-existing antibody compared to 34% in individuals born before 1950 according to A. Klimov at CDC (due for publication in NEJM [New England Journal of Medicine]). Question 3: Comment on the 1976-77 “swine flu” vaccination program. Dr. Iskander responded: “A national vaccination program was conducted in 76-77, and the vaccine was rarely reported to cause a serious neurological illness. There are two main differences now: 1. The current strain of H1N1 is causing much more widespread disease, and is classified as a global pandemic. So, benefits of vaccination are likely to be much greater now than in 1976. 2. Flu shots given since 76-77 do not appear to cause serious illness. Even if they do so rarely, it is likely that the benefits would outweigh the risks for most patients. Question 4: What is the incidence of Guillain-Barre syndrome with traditional seasonal flu vaccines? Is the expected 1-10 per million higher than what is generally seen with the seasonal vaccine? Dr. Iskander responded: “Since the 76-77 swine flu vaccine, most carefully done studies have not found an increased risk of GBS following flu vaccine. Those few studies that have found a risk are on the order of 1 additional case per million persons vaccinated. So, very rare.” Question 5: “In the questions materials it is stated that the 'most effective' treatment for the flu is vaccination. Can you please explain what allows you to draw that conclusion?” Dr. Malinoski responded: “I did not write the questions and indeed vaccination is not a treatment but a prevention strategy. If you change the question to reflect this, the answer is vaccination is the most cost effective approach to disease management across most all infections, not just influenza. There is a wealth of data on this. Of course, particularly with influenza, the match between the strains that circulate and the vaccine is a very important element of success.” Question 6: “How will the H1N1 vaccine be distributed? Dr. Malinoski responded: “The government will distribute vaccine through a central distributor, McKesson, which is already familiar with vaccine distribution as they are involved in distributing vaccines for children who receive vaccines through public clinics (the VFC program). Distribution is planned based on population and will go to both private and public groups participating in the administration of vaccine.” Question 7: Where is the seed obtained for the novel H1N1 vaccine? Dr. Malinoski responded: “The novel H1N1 vaccine is derived from stock virus that is a recombinant or reverse genetics construct that ‘moves’ the California/07 hemagglutinin and neuraminidase (H and N genes) into the ‘backbone’ of gene segments from strains capable of replicating in eggs and, in the case of the live attenuated intranasal vaccine, adds the correct sequence of those N and H genes to the attenuated (weakened) genes of the vaccine master seed.” Question 8: Who is making the novel H1N1 vaccine? Dr. Malinoski responded: “Five manufacturers have been contracted to provide bulk vaccine. These are CSL, Novartis, GSK, sanofi-Pasteur, and MedImmune. MedImmune will provide the live, attenuated intranasal vaccine. The others will provide bulk of single and multidose versions of the injectable subunit vaccine. All bulk subunit vaccine will be filled by CSL in their filling facility and the plan is to have a single distributor, McKesson, distribute vaccine in the same way they currently distribute vaccines for children in the US. This assumes that all manufacturers will be successful in making vaccine (MedImmune has publicly confirmed they have completed their production, others have not yet confirmed).” Question 9: Comment on the following vaccination scheduling questions: 1) With non-pandemic seasonal flu, we continue to vaccinate even after the peak of flu season has passed, and even into March. Is there future immuno-benefit when faced with the same strain in a subsequent season? 2) If so, would this be of benefit in preventing future H1N1 pandemics? 3) Are past recipients of H1N1-like containing vaccines likely to have some immunity to the currently circulating virus? Dr. Malinoski responded: “These are insightful observations and questions. Here are some answers: 1. We cannot always predict when a flu season will come and go and, indeed, we may have one A strain at one time of year and the other A or the B strain later, so even if one strain has passed, the risk of the others continues, hence the importance of immunizing as long as possible. the evidence of protection lasting from say March into the following year is not very robust. But it makes sense that it might occur, provided the strains haven't changed. 2. For novel H1N1, the expectation is that we will likely have at least 2 years with this strain and the advantage to a continued vaccination effort is to first ensure antibody levels are high enough to provide optimum protection but, more importantly, to get the percent coverage to the highest possible level. 3. Unfortunately the data generated by the CDC and others show that the recent H1N1 vaccines do not induce antibody to the novel H1N1 vaccine. However, at least 1/3 of people who were born before 1954 seem to have antibody (likely from natural infection between then and now). Hence the recommendation that those over 64 will have natural infection. This is evidence that natural infection helps prevent disease (at least with the same strain) and that the live, attenuated vaccine is an effective vaccine as well.” Question 10: What role do antivirals play a role now that a vaccine may be available? Dr. Malinoski responded: Below is the latest guidance from the CDC (issued on 6 May 09) related to antiviral prophylaxis (pre- or post-exposure). The document also recommends treatment with antivirals in anyone hospitalized with H1N1 and anyone at risk of severe complications. As for how this fits with a vaccine strategy, here are points to consider: 1. The decision to use antivirals should be made by a qualified healthcare professional who will consider the specific situation of the patient’s health and risks around influenza. Remember these medicines are not benign and carry their own risks. 2. Another reason to restrict antivirals use relates to helping to prevent the development of resistance. If there is broad use of antivirals there will be more ecologic pressure to select for antiviral resistance, leaving subsequent patients without any treatment options. Indeed, resistant isolates of novel H1N1 have been found from people receiving antivirals although, fortunately, these do not seem to have spread thusfar. 3. In the absence of vaccine then while waiting for vaccine to be made available serious consideration should be given to the use of antivirals in appropriate populations. 4. Once vaccine (that we are confident will induce protective immunity) is available, it is clearly the more cost effective approach to controlling the spread of disease and protecting ourselves. ---------------- CDC Guidance of 6 May 2009: “Post exposure antiviral chemoprophylaxis with either oseltamivir or zanamivir can be considered for the following: Close contacts of cases (confirmed, probable, or suspected) who are at high-risk for complications of influenza. Health care personnel, public health workers, or first responders who have had a recognized, unprotected close contact exposure to a person with novel (H1N1) influenza virus infection (confirmed, probable, or suspected) during that person’s infectious period. Information on appropriate personal protective equipment is available at: Interim Guidance for Infection Control for Care of Patients with Confirmed or Suspected Swine Influenza A (H1N1) Virus Infection in a Healthcare Setting and might be updated frequently as additional information on transmission becomes available. Pre-exposure antiviral chemoprophylaxis should only be used in limited circumstances, and in consultation with local medical or public health authorities. Certain persons at ongoing occupational risk for exposure who are also at higher risk for complications of influenza (e.g., health care personnel, public health workers, or first responders who are working in communities with influenza A H1N1 outbreaks) should carefully follow guidelines for appropriate personal protective equipment or consider temporary reassignment.” Question 11: Comment on the genetics of influenza. Dr. Malinoski responded: “First, influenza viruses are made of RNA, and not DNA. This is important because the mutation rate in RNA is very high, thus influenza viruses change their genetic structure quickly and easily, resulting in many different forms causing disease. Secondly, we know that we can help protect against influenza by immunizing people with the surface coat protein hemagglutinin (H) but that protection is very specific to the strain (e.g. H1 does not protect against H2, etc,., and there are 16 different H types in nature (not all infect people). Worse, within a given H type (e.g. H1) different strains can avoid protection (so the H1 in this year's seasonal vaccine doesn’t protect against novel H1N1). So, given the ease with which genetic changes can occur and the advantage a new virus can have in avoiding immunity from an old virus strain, we see what is called genetic drift from year to year which is why we have to change the vaccine often, to account for that drift (or escape if you will). Every few decades we have seen major changes in the surface protein resulting in pandemics that cause widespread disease (pandemics). This is caused genetic shift. What’s novel about the novel H1N1 is that genetically it appears to be a drift but in many ways it is behaving as one would expect from a shift. So, here’s the short answer to your questions: 1. Making a new vaccine is a challenge for every strain every year. What’s hard is getting a strain that will grow in eggs but produces the desired H1N1 (manufacturing involves using live viruses to infect eggs and then harvesting the virus and purifying the components). Question 12: Is it correct that 159 million doses of vaccine will be needed to administer round 1 to the target groups? Is it also correct that before round 2 will begin, the >65 group will be in line for round 1? Is there a predicted time frame for when the 2nd dose should be administered? Can the non-target groups be covered before it is ‘time’ to begin round 2? Do we expect to have an adequate supply to cover the moderate approach or the full throttle approach, if implemented, in 1 or 2 dose regimens? Dr. Malinoski responded: “In Reply: Question 13: Of course the patient’s immune status is the best predictor of the likelihood of complications but is there any data or history that supports prediction of the most common secondary infections in those susceptible (for example MRSA pneumonia)? Dr. Malinoski responded: “Interesting, influenza illness is not historically an opportunistic infection that defined HIV/AIDS patients. But, your question is about who’s at risk of severe disease with H1N1 and the complications reported with MRSA. In the original report in the MMWR on an outbreak of community acquired MRSA pneumonia (http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5614a1.htm?s_cid=mm5614a...) the risks were identified as having cavitary infiltrates or a history of MRSA infection. But this is just one example of the risks associated with influenza. There are likely to be other factors associated with MRSA complications that are yet to be identified. Clearly, as a lower respiratory tract infection, influenza damages the respiratory tract and as such makes lung tissue more susceptible to infection by bacteria that previously may have only been colonizing the nasal passages or skin. But as a respiratory pathogen, influenza will be more severe in patients with pre-existing chronic lung disease, chronic heart disease, & diabetes where either circulatory or respiratory support is already compromised. Pregnancy is also a risk factor for related reasons. A recent (2001) article about such a survey can be found at the following link: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=57009.” Question 14: What about distribution of vaccines at the local level? Local emergency management and public health departments developed and exercised plans for mass distribution of prophylaxis under the HSEEP funding made available a few years ago. Counties, for example, partnered with colleges and universities to set up PODs. Full-scale exercises, funded under Federal FEMA Homeland Security Exercise Evaluation Program (HSEEP), were conducted in many jurisdictions. I’ve attached HSEEP Volume II as a reference tool used in many localities. These exercises should be repeated this fall to prepare for H1N1. HSEEP Volume I (PDF) HSEEP Volume II (PDF) Dr. Malinoski responded: “It is worth appreciating that while CDC has experts and makes recommendations their ‘authority’ is limited and it rests with state and local jurisdictions to develop and implement their plans. Obviously, states turn to federal authorities for funding and expertise to ensure they develop the best possible plans for their situation. Allocations of federal stockpiles of antivirals and other supplies do require state health departments submit requests for supplies from those stockpiles and the plans for novel H1N1 vaccine distribution include shipment from a central distributor (McKesson it seems) which will use the existing vaccines for children network and will determine volumes based on population estimates & estimates of the target populations by geography. Clearly where supplies are limited, there will be an effort to balance distribution to cover the needs and, for vaccine, the target groups. This is necessary to help avoid what happened back in 2003/04 flu season where the vaccine shortage was not managed centrally and some jurisdictions ended up with surplus vaccine while others were in desperate need. So, it is best to look to your own state for their guidance documents. As examples, the website for NC regarding vaccination plans is as follows: http://www.co.guilford.nc.us/publichealth/campaigns/wp-content/uplo... The website for Q&A for North Carolina regarding antivirals is as follows: http://www.epi.state.nc.us/epi/gcdc/pdf/avfaq-071509.pdf Question 16: What flu virus strains is the seasonal vaccine covering this year and how was that determined? Dr. Iskander responded: “A/Brisbane/59/2007 (H1N1)-like A/Brisbane/10/2007 (H3N2)-like B/Brisbane/60/2008-like The above listed are this year’s 3 strains included in the seasonal vaccine. An FDA advisory panel meets every February to make the recommendations for what strains to include in the following seasons vaccine, based on worldwide patterns of circulation of influenza viruses. The novel or pandemic H1N1 strain had not yet emerged at the time FDA had to decide on this season’s strains.” Dr. Malinoski responded: “The 2009/10 vaccine formulation contains the same A strains as were in the 2008/09 formulation and a new B strain (Brisbane-like) instead of the B-Florida strain used last year. Because vaccine production needs to start early in the year for August/September release, the Food and Drug Administration’s (FDA) and Related Biological Products Advisory Committee, in conjunction with recommendations from the World Health Organization (WHO) and Centers for Disease Control (CDC), makes recommendations for the strains to be used in February 2009. The WHO and CDC review cases of influenza disease that were seen around the world to try to predict what strains are emerging as most important for the coming year. Unfortunately, almost half the time there is not a perfect match from year to year. And for this year, the H1N1 disease occurred too late to change the strain for the seasonal vaccine, so we will have both a seasonal vaccine and the novel H1N1 vaccine to give to folks. Question 17: What initially caused the H1N1 to begin spreading during a time of year (springtime) that is not known as the “flu season”? Does it correlate to the northern/southern hemisphereds, or is this strain in particular the reason? Dr. Meltzer (economist) responded: “The participant is quite correct. Generally, new strains of influenza enter the U.S. population in the Fall and Winter seasons. It is extremely rare to see a new influenza strain enter the U.S. population and begin to circulate widely in the Spring season. However, when it comes to influenza pandemic strains, we have recorded in past pandemics the circulation of the pandemic strains in the Spring preceding the pandemic. Perhaps the most famous example is the cases of pandemic influenza that were recorded in U.S. Army training camps, in Kansa and other sites, in the Spring of 1918. It appeared that, during the summer of 1918, the pandemic strain disappeared, only to re-appear in the Fall and Winter of 1918-1919. So, it is not unexpected that a pandemic influenza strain “makes an appearance” in the Spring preceding the actual pandemic. Why this should be the case is a matter of debate, with no certain answers.” Question 18: How do we know if the influenza this fall is seasonal or novel H1N1? Dr. Meltzer (economist) responded: “In addition to my fellow panelist’s comments regarding testing for influenza, I do wish to assure everybody that the CDC does, and will continue to, test specimens to determine exactly what type of influenza is infecting people. To see the type of data generated, CDC’s weekly influenza report always includes a graph showing the percentage of specimens that test positive for influenza, and by what type of influenza (e.g., seasonal strains or novel H1N1) (graph available at: http://www.cdc.gov/flu/weekly/index.htm#EIPNVSN). It must also be emphasized, for reasons detailed in the reply from my fellow panelist, that not every person that visits a physician for influenza, or is even hospitalized, will have a specimen taken that will be shipped to a State public health laboratory or CDC’s laboratory. BOTTOM LINE: CDC will continue to test specimens collected from some patients, and categorize types of circulating influenza strains, allowing public health officials and the public to understand what strains of influenza is causing influenza disease in the population.” Question 19: How does this pandemic compare to the one in 1976? Dr. Metzger (economist) responded: I would, however, like to address the issue of the difference between the swine ‘flu ‘event’ of 1976 and the current threat poised by novel H1N1. In 1976, there was evidence of a new strain of influenza. But, unlike the current situation, when the vaccination campaign started in 1976, there were no reports and confirmations of widespread transmission in several communities. In 2009, as you know, there are reports of cases from around the world of tens of thousands of H1N1 cases. These reports include almost 8,000 hospitalizations and over 500 deaths in the U.S. alone (see: http://www.cdc.gov/h1n1flu/update.htm#totalcases). Thus, unlike 1976, we have a very definite risk of disease and widespread number of adverse events associated with an influenza pandemic. Question 20: Is vaccination the most effective “short term” solution because it has an immediate impact on transmission rates and an individual's response to infection? Would a longer term “more effective” solution be having individuals’ immune systems be strengthened through experience rather than external intervention? Short term more transmissions and greater infection rates but what would be the impact on the longer term capacity of the individual and collective immune systems? Dr. Moore responded: “Vaccination is preferable to allowing people to be infected and develop immunity from infection because it mimics the infection and generates protective antibodies while avoiding the risk of severe illness and death that comes with natural infection. Unfortunately, no one can be sure that influenza illness will not kill them. [sic] Each year there are influenza fatalities among previously healthy children and adults. Vaccination does generate protective antibodies that can last for a year or longer, which is longer than any particular strain of influenza circulates in a season. Because it works that way, it is both a short- and long-term solution.” Question 21: If neither the vaccine nor antivirals work, are there enough ventilators available nationwide to meet the need? Ms. Peters responded: At this time I do not think that there is a shortage of ventilators but that all depends on how many people get sick. If this is a Category 1 pandemic then there should be adequate ventilators but if it is Category 5 then there will be a shortage. I think in our State [Missouri] we have left the issue of vent allocation largely up to the hospitals to determine. Sorry that I do not have a more detailed answer for you. The content experts were pretty good, especially Dr. Malinoski (the consultant with vaccine manufacturing expertise) but do not represent the spectrum of stakeholders with expertise in the matter of H1N1 vaccination approaches. Except for Dr. Malinoski, all three physicians, the economist, and the epidemiologist in this group of content experts work for government-run public health organizations. The important voices and ideas of private-sector community health practitioners and academicians (e.g., Drs. Morens, Taubenberger, D.A. Henderson, Tom Inglesby, and Roz Lasker) were absent from the dialogue. The dialogue involved a non-representative sample of participants consisting of only 79 souls from across the U.S. One hopes that the CDC acknowledges the utter lack of generalizability of the poll results generated as to whether the vaccination approach should be GO-EASY, MODERATE EFFORT, or FULL THROTTLE (see SEMP Biot Report #646 at http://www.semp.us/publications/biot_reader.php?BiotID=646). The pros and cons—used as focus points--were weakly expressed and incomplete, in this author’s opinion. Notes:
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