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CME/CE

Vaccine Safety: What Does Experience Tell Us? Part 2

  • Authors: David Salisbury, MB, FRCP, FRCPH, MFPHM; Paul A. Offit, MD
  • THIS ACTIVITY HAS EXPIRED
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Target Audience and Goal Statement

This activity is designed to meet the continuing education needs of pediatricians and pediatric nurses.

To demonstrate how information gathered through long-term experience is used to monitor and enhance vaccine safety and increase confidence.

On completion of this CME offering, participants will be able to:

  1. Demonstrate the impact of public confidence and the global challenge that providers face in maintaining this confidence to ensure the success of immunization programs.

  2. Describe the extensive pre- and postlicensure monitoring and surveillance techniques used to ensure vaccine safety.

  3. Demonstrate an international perspective of safety concerns with regards to particular vaccines.

  4. Summarize the resources available and the communication techniques required to meet the needs of differing patient types who may require multiple sources of information.

  5. Review case examples, including measles, mumps, and rubella, as models to explain the impact of public confidence and the experience gained through monitoring and surveillance.

  6. Explain the significant impact vaccines have made on the morbidity and mortality of common childhood diseases.


Author(s)

  • Paul A. Offit, MD

    Chief of the Section of Infectious Diseases, Children's Hospital of Philadelphia; Henle Professor of Immunologic and Infectious Diseases, University of Pennsylvania School of Medicine, both in Philadelphia, Pennsylvania.

    Disclosures

    Disclosure: Dr. Offit has received honoraria related to specific research activities and product royalty/licensing fees from Merck & Co., Inc.

  • David Salisbury, MD

    Principal Medical Officer, Department of Health, London, United Kingdom

    Disclosures

    Disclosure: Dr. Salisbury has received no honoraria related to formal advisory activities, development of educational materials, speakers' bureau activities, or specific research.


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  • This activity for 1.1 contact hours is provided by the Institute for Continuing Healthcare Education, which is accredited as a provider of continuing education in nursing by the American Nurses Credentialing Center's Commission on Accreditation (ANCC-COA). This credit may be applied toward licensure requirements in states that recognize ANCC-COA-accredited providers. Accreditation applies solely to educational activities and does not imply approval or endorsement of any commercial product by the ANCC-COA.

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CME/CE

Vaccine Safety: What Does Experience Tell Us? Part 2

Authors: David Salisbury, MB, FRCP, FRCPH, MFPHM; Paul A. Offit, MDFaculty and Disclosures
THIS ACTIVITY HAS EXPIRED

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Vaccine Safety: The United Kingdom Experience, Presented by David Salisbury, MB, FRCP, FRCPH, MFPHM

Managing Adverse Events Related to Vaccine Use

  •  
  • Vaccine Safety: The United Kingdom Experience

    Slide.

    Vaccine Safety: The United Kingdom Experience

    (Enlarge Slide)
  • I am going to talk a little bit about how we actually monitor and measure adverse events.

  • Interpreting and Misinterpreting Vaccine Adverse Effects

    Slide.

    Interpreting and Misinterpreting Vaccine Adverse Effects

    (Enlarge Slide)
  • But much more, about how we manage the problem of adverse events. So first of all, what do we do? Well, you've heard a very detailed account of the surveillance system in the United States, and I'm not going to go into that sort of detail. We have routine surveillance for vaccine-associated adverse events, we have special studies available to us, and we also have to manage adverse events, and I'm going to go through each of those in turn. So what about the routine surveillance?

  • Adverse Events in the UK

    Slide.

    Adverse Events in the UK

    (Enlarge Slide)
  •  
  • Routine Surveillance for Vaccine-Associated Adverse Events

    Slide.

    Routine Surveillance for Vaccine-Associated Adverse Events

    (Enlarge Slide)
  • Well, our "yellow card" system was set up in the light of the thalidomide tragedy and it was set up in the 1960s. Yellow cards are available to all doctors, to dentists, to coroners, and for our recent meningococcal C vaccine campaign available to nurses, hitherto nurses have not been reporting adverse events. We have a passive surveillance system, it admittedly underreports, but it is more likely to identify severe reactions than minor ones, and any severe or fatal reactions are followed up, and for our meningococcal C campaign, we've tried to put together a Causality Assessment Committee and have found this just as difficult as everybody else who tries to assess causality. The point about the "yellow card" system, very much like the VAERS system, is that it allows hypotheses to be generated that then need to be tested elsewhere. These special studies that we have are things that come about because of the privilege that we have within our health system.

  • Routine Surveillance for Vaccine-Associated Adverse Events

    Slide.

    Routine Surveillance for Vaccine-Associated Adverse Events

    (Enlarge Slide)
  • The first is that every child in the country is on an immunization register, and so we have a nationwide database that covers the immunization of every single child. So if these immunization registries are used in conjunction with the data set from hospital episode statistics, then we can start to link what happens with immunization, and what happens with the hospital admission, and you can then look at the attributable risk, the one being caused by the other. We also have a general practice research database so that every event within primary care in a subset of the population can also be extracted and then the immunization can be linked in with the clinical events. So what have we done with this sort of linkage? And the point about this linkage is that it allows you to estimate attributable risk. We've looked at the attributable risks of convulsions or seizures after MMR. We've looked at the attributable risk of aseptic meningitis after the Urabe or the JL MMR vaccines. We've looked at the attributable risk of acute encephalopathy after MMR.

  • Special Studies (PHLS)

    Slide.

    Special Studies (PHLS)

    (Enlarge Slide)
  • We've looked at the attributable risk of thrombocytopenia purpura after first or after second doses. We've looked at MMR and autism, and here we didn't use the same data sets. What we used for this was a subset of the register where not only do you record the immunization, but there are also special needs data sets. So any children who have special educational needs are registered on the registry, and that means you can then start to link their presence on a register for special needs with their immunization status. We've done similar studies looking at the attributable risk of convulsions following the addition of Hib to DTP vaccine. When Hib was introduced, there appeared to be an increase in the number of seizures that were occurring in children after they had received that vaccine. But when you looked at the attributable risk, not through the passive surveillance system but through data linkage, you found that there was zero attributable risk of seizures after Hib vaccine. And we've also looked at the attributable risk of invasive infection following MMR as an indication of the immunosuppression that could occur, and we've looked at OPV and intussusception as well. So we have extensive experience of using record linkage to estimated attributable risks.

  • Special Studies (PHLS)

    Slide.

    Special Studies (PHLS)

    (Enlarge Slide)
  • I need to move onto what I think is the more interesting part of the presentation, and that is managing adverse events, and I'd just like to highlight key points and then I'll open each of them in turn. The first is that adverse events occur rarely, but they do attract considerable concern. Serious adverse reactions occur extremely rarely, and when they do occur, they are a cause for concern. The next point is that most of our knowledge, most of the data on adverse events or on reactions does not justify, in fact, the importance that is attached to it in terms of causal validity. In other words, we have a considerable amount of information, but that information is very rarely explicit that it has caused what has been reported. And when we set it against the benefits, then it's very small there compared with the benefit if the case is prevented. And then I think it's important that we should focus on this point, that all purported adverse reactions should be tested against the criteria of biological plausibility, independent evidence that corroborates the association, or evidence of an increased risk of the association in immunized compared with unimmunized individuals or groups. Those are important criteria that we should always bring to mind whenever somebody says, "I've seen a really adverse reaction after that vaccine," and you should test it against those criteria.

  • Managing Adverse Events: Key Points

    Slide.

    Managing Adverse Events: Key Points

    (Enlarge Slide)
  • So what about the key points then? Stamp collections, those are those many reports that get published in our professional journals, that say I've seen six cases of this reaction. Stamp collections should not be taken as evidence in support of an association. They may form the basis of a hypothesis that should be then tested by a properly designed study, and I'll show you some examples of stamp collections. Vaccine scare stories usually do have some quasi conventional scientific starting point. They start from somewhere. And the last point, which is penultimate, publication is not proof, and the last of my key points, is that scare stories have legs and I'll show you each of these.

  • Key Points

    Slide.

    Key Points

    (Enlarge Slide)

Stamp Collections and Examples

  • But first the stamp collections. What are they? Well, it's a series of cases, often collected through active searching when you go looking for them, with little relevance to the background risk, and they are very vulnerable to the development of posthoc hypothesis generation, and here's an example. In 1994 in the UK, we ran a nationwide immunization campaign with measles-rubella vaccine, when we immunized all school children, age 5 up to 16, in the space of a month, and that was, I think, about 7 or 8 million kids. There was a cluster of cases of Guillain-Barre syndrome occurring postimmunization. They were reported in newspapers, they were reported through passive surveillance, and posthoc, there was a hypothesis that there might be a causal association between measle vaccination and Guillain-Barre syndrome. We tested that independently and we tested it by coming to this region, to the region of the Americas, and actually south of the Texas-Mexico border because we compared the risk of Guillain-Barre syndrome detected through acute flaccid paralysis surveillance in periods after measles vaccination campaigns in Central and South America, and we compared the campaign periods against non-campaign periods, and we demonstrated that there was no significant risk of Guillain-Barre syndrome after measles vaccine. So a stamp collection could have very easily been published, but the independence we tested was shown not to be correct.

  • Stamp Collections

    Slide.

    Stamp Collections

    (Enlarge Slide)
  • So here is one of the world's most famous stamp collections. This is the paper that led to the complete loss of public and professional confidence in pertussis vaccine. It was the ultimate stamp collection, 30 children, no background risk, no attribution.

  • Stamp Collection Example: Neurological Complications of Pertussis Inoculation

    Slide.

    Stamp Collection Example: Neurological Complications of Pertussis Inoculation

    (Enlarge Slide)
  • Here is another stamp collection, ileal-lymphoid nodular hyperplasia, nonspecific colitis, and pervasive-developmental disorder in children, A. Wakefield and others. There are 12 children in this study, there are 14 authors, and I think that probably says it all. There is no background risk. There is no attributable risk. It is a stamp collection.

  • Stamp Collection Example from The Lancet

    Slide.

    Stamp Collection Example from The Lancet

    (Enlarge Slide)
  • Here is another stamp collection, but here the authors at least recognize that this is a stamp collection. Here they've taken children for whom claims have been made that their encephalopathy followed the receipt of an MMR vaccine. There is no background data and every child in this study has claimed for compensation, so they are all preselected, they have to be there because they are there. It gives no evidence, the background risk, it gives no insight into attributable risk, so stamp collections are, I would suggest, a dangerous thing. And remember when you were children, the best stamp collections have the most number of stamps and they had the biggest and brightest stamps, but they were not necessarily the most valuable stamp collections.

  • Stamp Collection Example

    Slide.

    Stamp Collection Example

    (Enlarge Slide)

The Origins of Public Concerns About Vaccines

  •  
  • It's Published So It Must Be True

    Slide.

    It's Published So It Must Be True

    (Enlarge Slide)
  • So next, it's published, so it must be true. So here is an article published in the Lancet, Is Measles Vaccination a Risk Factor for Inflammatory Bowel Disease? Well now the paper actually was awful. It compares non-comparable groups, it uses all manner of epidemiology inexactitudes, but it gained great credibility. So here, a few months later, is another paper if I can find it, a case-controlled study of measles vaccine and inflammatory bowel disease. What do we suppose that one showed? No association. When you do a properly designed epidemiological study, you find that there is no association between the vaccine and the disease.

  • It's Published So It Must Be True

    Slide.

    It's Published So It Must Be True

    (Enlarge Slide)
  • But what did the leader in that edition of the Lancet say? These findings provide no support for the hypothesis that measles vaccination in childhood predisposes to the later development of inflammatory bowel disease, and the real bit is the bottom bit, will this negative report be as well publicized as the 1995 study? Well, of course not. It was inconvenient to those who were very pleased to be able to say the vaccine caused inflammatory bowel disease, so the negative work rarely gets reported.

  • It's Published So It Must Be True

    Slide.

    It's Published So It Must Be True

    (Enlarge Slide)
  • So where does the public concerns come from? Well, they start in the medical journals, as I just pointed out to you. But then what happens? They get picked up by journalists and it starts with a fairly sensible headline, Measles Link to Growing Bowel Disease, and then watch the headlines. The next, we've got a scare over the measles jab, and then we've got the crying shame of the vaccination victims. This is all from the same publication. Now we've got an alert. Everybody has to be on alert over this vaccination.

  • Sources for Public Concern

    Slide.

    Sources for Public Concern

    (Enlarge Slide)
  • And now we've got a ban, "Ban the three-in-one jab," urge doctors. Now that really must make it very important because doctors are urging a ban. So where does it come from? It comes from the medical journals. Here is a doctor journalist who now blames the Department of Health, the fact that there hasn't been a Ministry of Health for about 20 years is clearly inconvenient to the headline writer.

  • Sources for Public Concern

    Slide.

    Sources for Public Concern

    (Enlarge Slide)
  • And now the parents are right, no evidence, but the parents are right. And just occasionally, somebody writes the reality that the scare is pure moonshine, but those headlines are only too infrequent. So it starts in the professional press, but it doesn't take long before it takes off in the wider media.

  • Sources for Public Concern

    Slide.

    Sources for Public Concern

    (Enlarge Slide)
  • So scare stories have legs. So let me just show you. This starts in the Philippines. The government puts an anti-fertility agent into tetanus toxoid. Somebody tested tetanus toxoid to see if it had HCG in it. Now why would you do that? But they said it did. And the story went to Central America, denounced by the Cardinal, the vaccine that will sterilize. I told you about the MR story in the UK. One of the people who had Guillain-Barre was the son of a creditor from Barbados and so the Barbados newspapers ran the story that this child had been paralyzed by the vaccine, and it wasn't even true. Now the MMR scare started in my country, and ran in your Congress, and it took 48 hours after it ran in Congress with no publication of the scientific data, simply people telling stories to a gullible audience. Forty-eight hours later, it bounced all the way back to our newspapers,

  • Scare Stories Have Legs

    Slide.

    Scare Stories Have Legs

    (Enlarge Slide)
  • and on Sunday morning, those were the headlines on one of our newspapers; no data, no science, no nothing. Scare stories have legs.

  • Headline: Measles Jab

    Slide.

    Headline: Measles Jab

    (Enlarge Slide)

Overcoming Media Reports and Public Concerns

  • So what are the principles that we use in trying to deal with all of this? The first is we try to predict, we try to prepare, we try to be proactive, and we try to achieve positive responses, and I'll show you these in turn. So what can you do about prediction?

  • Guiding Principle Used by Department of Health

    Slide.

    Guiding Principle Used by Department of Health

    (Enlarge Slide)
  • Well, we do have reasonable ideas, which topics are likely to attract public interest; thimerosal and mercury toxicity, not surprising, autism, multiple sclerosis, multiple vaccines and immune overload. We can anticipate these are likely to cause trouble. They share common features of an unknown etiology condition that the public fears. Often there is a long latency, and that makes the evidence to negate the claims all the more difficult to get. It will be almost impossible to set up new studies using immunized and unimmunized groups. We won't have unimmunized control groups after vaccines are introduced nationwide. And the lack of evidence from those proposing vaccine scares does not appear to hinder them at all. The public would expect us, the authorities, to prove the negative, or the theories stand unchallenged.

  • Predictions

    Slide.

    Predictions

    (Enlarge Slide)
  • So what can we do in preparation? Well, ideally the prediction would have identified the forthcoming problem, and it's possible that routine information sources will suffice to give answers, but it is more than probable that they will not give the answers. So critical is the phase of intelligence gathering. Does adequate data already exist that can answer the problem? And it may be that that data is already there. How feasible is it to collect new data? And here very important, how much can you find out about the cards in other players' hands? Most of these people are so proud of their claims that they'll tell you all about their experiments if you just ask, but remember that you're starting from behind in all of these scare stories. If you need to set up studies to counteract the scare, it's unlikely that you will have the answers in time, and an answer that we are awaiting these studies does not reassure anybody.

  • Preparation

    Slide.

    Preparation

    (Enlarge Slide)
  • So what can you do to be proactive? Well, the first is that uninformed health professionals will undermine your efforts. It may be difficult to alert health professionals as promptly as they would wish because of embargoes on publications. Many of us often know about material which is about to appear in a journal, but we cannot tell the world because there is an embargo on it. You have to appreciate that doctors hate finding out about vaccine scares from their patients. It's not difficult for journalists to find one doctor who will give unhelpful comments, often based on ignorance, but that is irrelevant. You should provide health professionals with multilayered information, both for themselves and for them to use with parents, and wherever possible, you should involve independent experts who can endorse your response. You should share the problem if possible, so you can present a broad coalition.

  • Proactive Steps

    Slide.

    Proactive Steps

    (Enlarge Slide)
  • So what about proactive? Well, prepare information materials for parents on many levels, for all audiences. Give references to parents. If you've quoted a piece of work, give the parents the reference, they add credibility, and actually they're very rarely followed up, but it doesn't matter. It at least shows that you're not just giving opinions. Test all materials that you use for parents and health professionals before you print a million leaflets. What makes sense to you and looks attractive may be useless in getting a message across. Try to find ways to target your information to the right health professionals, and more importantly, to the right parents at the right time, and I'll show you some of that in a moment. If you brief friendly journalists, remember that they cherish their independence, they're always going to show both sides of a story. The critical issue is where do they draw the line?

  • Proactive Steps

    Slide.

    Proactive Steps

    (Enlarge Slide)
  • So what have we done to be proactive or be responsive? So here is an example of how we sent a letter from the Chief Medical Officer to every single doctor in the United Kingdom, measles-mumps-rubella vaccine, Crohn's disease and autism, and the point here is that this letter, which is about six sides long, demolishes a whole lot of the arguments about an association. I would have been mortified if my work had been so criticized.

  • Slide.

    (Enlarge Slide)
  • Now here's an information leaflet we can use for parents where we go through the arguments about MMR, autism, and bowel disease and so on. This was pre-tested before we ever issued it, and then tested afterwards. This is sent through the computerized register system, so that whenever a child is being called for their MMR immunization, this leaflet can be inserted in the call-up letter, goes by post, direct to the parent, before they bring their child for immunization, so the parent already has read the information by the time they come to the primary care physician.

  • Leaflet

    Slide.

    Leaflet

    (Enlarge Slide)
  • So what about positive responses? Tell the truth, give clear messages. While parents want to feel that they're making a choice, very few will be sufficiently informed to actually be making a fully informed choice. Unless they have degrees in epidemiology, statistics, immunology, virology and bacteriology, and vaccine design, manufacturing, quality assurance and quality control, it's unlikely that they will actually make an informed choice, but they like to feel that they're doing that. Risk assessment by parents and many health professionals implies a degree of rationality which is usually absent. If you say to someone the risk is one in a million, do they interpret that differently to a risk of 1 in 100,000? As soon as you put a number on a risk, you validate the risk; you give a veracity that there is a risk. We know that's not what the statistics mean, but it's not interpreted that way. I believe we should not offer a choice of risks. If you say to people the risk after the vaccine is this, the risk after the disease is that, and it's far better to have the vaccine than the disease, that doesn't mean anything to parents who have never seen measles, have no perception, and for whom it actually is not a real fear because most parents' children will never get measles now. So this business about saying here's the risk, here's the benefit is very difficult to put into realistic terms within peoples' lives. Do not patronize. To say we're the experts so you can believe us, goes down like a lead balloon. The expertise of anybody called doctor by a journalist is considered as credible as anybody else called doctor, and you can always find a doctor who'll say something different. A professor can be a bit tricky. People know that professors are important, but they're always thought to be a bit too brainy, so don't use too many professors.

  • Positive Responses

    Slide.

    Positive Responses

    (Enlarge Slide)

A Planned Response to Misinformation on a Vaccine

  • I'm going to end on the example about how we don't have to lose this war. Here is a headline in one of our newspapers at the end of August this year. On Saturday afternoon, this was a Sunday newspaper, on Saturday afternoon the journalist contacted us, and it was perfectly clear that he neither wanted to hear the truth, or if we told him the truth, he didn't understand the truth. And he told his readers that there was a coverup, that a new vaccine had killed 11 children, and that we had covered up the information. The fact that it was publicly available to him or anybody else was irrelevant.

  • Headline

    Slide.

    Headline

    (Enlarge Slide)
  • Within this same newspaper was this headline, albeit on the back page. After a few days when we heard that he was going to run this story again the week later, we decided that we would turn this around and be proactive. A newspaper a couple of days ago, this was the kiss of death. If the government denies links, you know there has to be links.

  • Headline

    Slide.

    Headline

    (Enlarge Slide)
  • But over the next 2 days, we decided we should stop this. This was no reason for a good vaccine to be damned unfairly, and so we went on to a very positive approach. We released all of the most up-to-date information on just how effective this new vaccine had been, and we got multiples of coverage in all of the newspapers, far, far greater coverage then was ever achieved by the one sour article from the week before. We got enormous amounts with television, the radio and all media coverage. So you don't have to lose this because the news that we have is enormously good news, but we've got to manage all of that in an effective way.

  • Headline

    Slide.

    Headline

    (Enlarge Slide)
  • I leave you with this comment. The irony of the Information Age is that it has given new respectability to uninformed opinion, and that was made in 1995 here in the United States, at a time before the Internet had really taken off. Now we have got that multiplied many logs over, and we have to deal with uninformed opinion that believes that it should be taken seriously. We have to show that our case is a better case, so I hope I have given you some insight into where some of these problems come from and how they can be actively managed.

  • The Irony of the Information Age

    Slide.

    The Irony of the Information Age

    (Enlarge Slide)