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Reflections of a Vaccinologist: Lessons Learned About What We Can Do to Improve Trust in Vaccines and Vaccine Programs

Wednesday, 29th of March 2017

Excerpt below; full text is at

https://academic.oup.com/jpids/article/6/1/3/2957334/Reflections-of-a-Vaccinologist-Lessons-Learned

Reflections of a Vaccinologist: Lessons Learned About What We Can Do to Improve Trust in Vaccines and Vaccine Programs^a 

Neal A. Halsey

Stanley Plotkin is well known for developing a rubella vaccine and other vaccines, founding the Pediatric Infectious Diseases Society, being a founding editor of the journal Vaccine, founding and editing the textbook Vaccines (currently in its sixth edition), and making many other significant contributions to vaccinology. Many people do not know that he also conceived the idea for the international advanced vaccinology (ADVAC) course taught annually in Annecy, France, for the past 16 years. Plotkin also provided an example of how to address safety concerns with his eloquent science-based rebuttal of allegations that his trials of oral polio vaccine (OPV) in West Africa in the 1950s were a source for the human immunodeficiency virus (HIV) pandemic [1]. The true history of acquired immunodeficiency syndrome (AIDS) [2] includes misguided policies and public health programs that contributed to the amplification of HIV, including the inappropriate reuse of needles and syringes. We need to acknowledge and learn from past mistakes.

Mistrust of vaccines and immunization programs has resulted in vaccine refusal and disruption of immunization efforts [3, 4]. Suspicion about OPV in Nigeria stopped polio vaccination for 13 months in 1 district and enabled the exportation of wild-type polio to at least 26 countries [5]. The World Health Organization deserves credit for overcoming these concerns and persevering in the global eradication effort; there have been no cases of wild-type polio paralysis in Africa for 8 months, which leaves Pakistan and Afghanistan as the last problem areas [6]. In Pakistan, a bogus immunization program set up by the US Central Intelligence Agency to look for information about Osama Bin Laden led to mistrust of immunization programs and resulted in the murder of at least 65 healthcare workers, perhaps the greatest mistake our government has made in in the field of immunization [7, 8]. The fake immunization program contributed no information that aided in bringing down Osama Bin Laden and has resulted in mistrust of internationally based immunization programs in many countries. In the United States, OPV caused 6 to 10 cases of vaccine-associated paralytic polio each year in the 1990s, which contributed to mistrust of vaccines until it was replaced by the safer inactivated polio vaccine, enhancing public confidence in vaccines. After many years of delay caused by false beliefs about the vaccine, inactivated polio vaccine is now being added to every countrys immunization program, which will enhance immunity to polio and prevent many of the more than 250 cases of OPV-associated paralysis that occur each year.

Plotkin was motivated to work on rubella vaccines by the 1963–1964 rubella epidemic, which resulted in 20 000 cases of congenital rubella syndrome (CRS). The RA27/3 vaccine that he developed is more effective and safer than other rubella vaccines [9]. This vaccine prevents clinical disease caused by rubella and CRS. It is ironic, and tragic, that some parents are currently withholding the measles, mumps, and rubella (MMR) vaccine from their children because of concerns that the rubella vaccine virus was isolated from an aborted fetus. That 1966 abortion took place because of rubella contracted during the pregnancy. Rubella vaccines prevent abortions by preventing rubella at all ages. Another ironic reason that parents withhold the MMR vaccine is their false concerns about it and autism; the MMR vaccine actually prevents CRS and the autism associated with it.

Witnessing deaths from measles in Nicaragua and North Dakota taught me about the severity of this disease and introduced me to the power of epidemiology to answer public health questions [10]. We introduced the measles vaccine to Haiti in 1982, where baseline studies revealed that one third of all children had had measles by 12 months of age [11]. Administration of the measles vaccine induced protective antibody responses in many children between 6 and 11 months of age, but response rates did not reach 100% until 12 months of age because of the interfering effect of maternal antibodies. Follow-up studies revealed survival rates in vaccinated children that were higher than those who were unvaccinated [12]. But then we overreached. As part of a World Health Organization–led effort conducted in several countries we learned that the interfering effect of maternal antibodies could be overcome by using vaccines of 100-fold-higher titer, which resulted in a 90% response rate at 6 months of age [13–16]. However, follow-up studies in West Africa revealed that the survival rates in girls who had received the high-titer vaccine were lower than those who received standard-titer vaccines, but there was no difference for boys [17]. Our subsequent studies in Haiti found the same pattern of differential mortality rates according to sex, which resulted in termination of the recommendation for high-titer vaccines [18]. The increased mortality rates were found only in countries with infant mortality rates greater than 100 per 1000 [19]. Our studies revealed some subtle decreased responses on tests of cell-mediated immunity in female recipients of the high-titer vaccine, but others believe that it was a protective effect of the standard-titer vaccine that was not observed with high-titer vaccines [17, 20]. The lessons we learned from high-titer measles vaccines indicate that safety in one population is not necessarily evidence that the safety levels will be the same in all populations. This experience indicated that dose is a factor to be considered in vaccine safety. One of the unfortunate consequences was the carryover concern that other vaccines and perhaps multiple vaccines administered simultaneously may adversely affect the immune system, including the false belief that giving several vaccines simultaneously can harm the immune system. The effect we observed was most likely limited to measles, because the measles virus directly infects lymphocytes.

Measles vaccines prevent at least 1 million deaths per year [21], so it is particularly disheartening to see the resurgence of measles in the United States, with 668 confirmed cases in 2014 and 162 cases confirmed as of April 17, 2015. Many of the children in these outbreaks were unvaccinated, most commonly because of a parents/guardians personal belief against or philosophical objection to vaccines. The fact that unvaccinated individuals pose a risk of transmitting measles and other diseases did not capture public attention until the Disneyland outbreak, which resulted in 147 cases in 7 states [22]; California was hit hardest with 110 infected, of whom at least 47 were unvaccinated. A few cases of infection were a result of vaccine failures, some of the children were too young to be vaccinated, and at least 10 of the infected were adults, including several employees at Disneyland, who most likely contributed to the outbreak. The important lessons learned included the public understanding that unvaccinated individuals pose serious risks to children who cannot receive vaccines and that unvaccinated children can grow up to be susceptible adults and contribute to outbreaks of disease in settings such as Disneyland. All employees of places where children congregate, including Disneyland and schools, should be immune to measles. The index patient in the Disneyland outbreak was a child whose parents deliberately withheld the MMR vaccine; when the family traveled overseas, the susceptible child contracted measles. Measles cases have been reported in every month of the year for the past 8 years in most regions of the world, and Europe has been the source of many of the introductions of measles into the United States in recent years [22, 23]. In the past few years, Europe has had several thousand cases of measles each year. Most European countries do not have immunization requirements for children to attend school, and the unwarranted scares about MMR vaccination and autism have decreased acceptance of the vaccine. The autism scares have been thoroughly refuted, but it took 12 years before the 1998 Lancet article [24] was retracted. The scientific community quickly recognized the bad science from this study [24–26], but it took an investigative reporter to uncover the undisclosed conflicts of interest and the fraudulent science. The effects persist. In 2015, 25% of persons aged 18 to 37 years in the United States believed that vaccinated children are more likely to have autism than unvaccinated children [27].

Bad science persists and is included in the marketing of many products, such as cosmetics and nutritional supplements [28]. We cannot expect the general public to recognize bad science, but we can do a better job of reporting in medical journals. Assumptions of causal relationships in case reports based on temporal associations continue [29]. Reports of unexpected serious illnesses after vaccines have resulted in the termination of national immunization programs for the prevention of hepatitis B, Haemophilus influenzae type B, human papillomavirus, pneumococcus, and MMR [3, 30, 31]. Instructive case reports are an integral part of our medical education and are included in highly respected journals. Case reports are a form of storytelling, which has been used for teaching since the beginnings of recorded time in cultures throughout the world. The science of clinical trials has improved by the implementation of standard requirements for reporting outcomes [32]. We should establish standards for case reports that include standards for assumptions of causal relationships for vaccines and drugs. The Clinical Immunization Safety Assessment network has established an algorithm for the assessment of causal relationships for individual adverse events after immunizations [33]. The algorithm requires a series of questions to be asked in a logical sequence and branching answers that lead to conclusions describing the assessment in understandable and scientifically correct terms. A consortium of journal editors should establish standard guidelines for reporting causality in case reports.

Institute of Medicine (IOM) reviews of vaccine safety have been the ultimate authority in assessments of causal associations between adverse events and vaccines [34]. The IOM starts from a neutral position, weighs the evidence, and sets a high bar for concluding that the evidence supports or rejects a causal relationship. For 133 (85%) of 156 associations the committee was asked to review in 2012, its conclusion was that the “evidence was inadequate to accept or reject a causal relationship” [34]. The common translation of this conclusion is, “We just dont know,” which opens the door for assumptions that there is plausible evidence to support a causal relationship, but it is not conclusive. When there is evidence against a causal relationship, but it is not strong enough to be convincing, would it not it be better to say, that the available evidence does not support (or suggest) a causal relationship? It takes many months for these reviews. It would be better to have a standing committee to respond quickly to concerns as they arise.

The 2009–2010 H1N1 influenza immunization campaign stimulated interest in vaccine safety and the need to coordinate safety information. The National Vaccine Program Office established a committee to review studies from multiple federal agencies [35]. This forum allowed for open discussions and sharing of study methods and preliminary data as the response evolved. Although several signals of possible relationships between adverse events and the vaccines were identified and openly discussed [35], a standing committee should be maintained to provide a forum for addressing questions about vaccine safety and helping to address these questions in a timely manner as they arise.

Support for postlicensure vaccine safety studies performed to answer questions that arise has been lagging. The Centers for Disease Control and Prevention Immunization Safety Office receives approximately $20 million/year, or 0.5% of the approximately $4 billion it receives each year, to support the purchase of vaccines and vaccine programs [36]. Funding for vaccine safety has been stagnant for many years and has not kept pace with the expanded number of vaccines and vaccine safety questions that arise. If we are to maintain public confidence in vaccines, we need to provide support to answer the many vaccine safety questions. Also, the successful Clinical Immunization Safety Assessment fellowship training program in vaccine safety has been terminated [37]. How are we going to maintain expertise in vaccine safety if we do not train additional professionals?

Walt Orenstein organized the first assessment of the effectiveness of school immunization requirements for the prevention of measles. The incidence of measles in the 1972–1973 and 1973–1974 school years was approximately 50% lower in states that had mandatory school-entry requirements than states that did not have requirements [38]. Now all 50 states have school-entry immunization requirements. All the states allow for medical exemptions based on contraindications to vaccines, and 48 states permit religious and/or philosophical or personal-belief exemptions [39]. It is not surprising that children who receive such an exemption are at much higher risk for measles and pertussis than children who are not exempted [40, 41]. The overall rate of exemption has been gradually increasing, primarily in states with philosophical or personal-belief exemptions [42]. The greatest increases have been in states with easy-to-obtain exemptions, and some states, including California, have a simple checkbox for opting out of requirements based on personal belief. In states with difficult-to-obtain exemptions, the rate has not increased. In 2002, a federal judge ruled the religious exemption in the state of Arkansas to be unconstitutional because the state picked which religions warrant a religious exemption. A model law that required documentation of a deeply held personal belief and counseling by a physician of the risks was developed with public-health legal experts [43]. However, Arkansas legislators had an easy checkbox for permitting exemptions, and the rate of exemptions doubled within a few years [44]. The rate of medical exemptions decreased by approximately 50%, which suggests that some children who had received a medical exemption were now getting a personal-belief exemption. In a review of 2 other states that allowed only religious or medical exemptions, the reason for the medical exemption was not made for a true contraindication to the vaccine (N. A. Halsey, unpublished data). Pediatricians could assist their local and state health departments and schools by offering to review requested medical exemptions and help educate other physicians and the public about true contraindications to vaccines.

The Disneyland measles outbreak resulted in increased public understanding of the risks that unvaccinated children pose to the community. The term ”herd immunity” is a misnomer, because people are not a herd, and unvaccinated children with valid medical exemptions who are protected by high immunization levels are not immune. A better term is “community protection.” The book On Immunity [45] describes how a mother came to understand vaccines, community protection, and the need to accept vaccines for her child. The author described the anguish faced by parents of feeling responsible for protecting their children against all possible exposures that could cause harm. Anxiety is created by the fear that he or she will miss something that could cause harm to the child. Parents going through the same uncertainties about vaccines would benefit from reading this book.

California, with support from the American Academy of Pediatrics, recently removed all nonmedical exemptions from school requirements for immunization on the basis of a recommendation from the Committee on Practice and Ambulatory Medicine and the Council on Community Pediatrics, which concluded, “Pediatricians should work individually and collectively at the local, state, and national levels to ensure that all children without a valid contraindication receive all childhood immunizations on time” [46]. Pediatricians would like to see all eligible children protected against preventable diseases. However, there was no mention of religious or other exemptions in the statement, and there was no discussion of the possible negative consequences of omitting these exemptions. This statement does not seem to have been reviewed by the Committee on Bioethics or the Committee on Infectious Diseases. Removing nonmedical exemptions will result in an interesting social experiment. Similar bills have been rejected in Oregon and Washington, and a bill introduced in Maryland has been tabled. There is concern that removing all nonmedical exemptions could result in a public backlash against immunization programs and public health authorities. Larry Gostin, a widely respected public health attorney and ethicist, urged caution by stating, “Harsh penalties could fuel public opposition to vaccine policy. The wiser course could be to require a rigorous process for claiming the exemption, relying on behavioral economics to encourage compliance” [47].

On April 19, 2015, Australia announced that it would no longer accept religious exemptions to immunization requirements for parents to receive reimbursements for child care, which range from 750 to 15 000 Australian dollars. The Christian Science religion was the only religion that Australia had allowed an exemption. The Minister for Social Services perceived a change in the Christian Science Church that allowed individuals to make their own decisions regarding healthcare. After reviewing their website, I am not convinced that there has been any substantive change in the teaching of Christian Science, but I am aware that lawsuits have been filed against the church. Paul Offits book [48] detailed many of the terrible decisions that parents have made on the basis of faith healing that have resulted in harm and death to their children.

All physicians who participate in possible changes to legislation should review the excellent review of religious concerns regarding immunizations by John Grabenstein [49]. Religious concerns include violation of prohibitions against taking life, violation of dietary laws, and interference with natural order by not letting events take their course. The RA27/3 rubella vaccine was isolated from the products of conception of a woman who had an abortion because of rubella during pregnancy. The MRC-5 and WI-38 cell lines used to grow viruses for several vaccines were derived from products of conception. These cell lines have been investigated thoroughly, are very safe, and have been used in the production of hundreds of millions of doses of vaccines. The Catholic Church has addressed the moral dilemmas that parents face with regard to immunizing their children with products that have any ties to past abortions [50]. The abortions were not performed with the purpose of obtaining materials used to produce vaccines. None of the fetal products are in the final vaccine preparations, and no additional abortions are needed to produce vaccines (a concept misunderstood by many parents). After a several-year in-depth review, the Catholic Church issued an official teaching concluding that being immunized does not involve any sharing in immoral intention or action of others, and parents have a moral obligation to provide for the life and health of their children by means of immunization. Other concerns about small amounts of pork products have been addressed by leaders in several religious organizations: the components have been sufficiently transformed from their original pork origins; the minute quantities per dose administered (eg, hydrolyzed gelatin and trypsin) invoke exceptions based on dilution; and/or vaccines are intended for medicinal purposes and are not a matter of ingestion, to which dietary rules apply. This information should be shared with families who raise religious concerns about these vaccines.

A poll in August 2014 revealed that 59% of persons aged 18–29 years believe that immunizations should be mandated, and that figure increased with age to 79% for persons aged 65 years or older (Figure 1) [51]. Another poll in early 2015 revealed that 84% of persons aged 18–37 years believe that vaccines are either safe or very safe, and the percentage increased with age to 92% for persons aged 69 years or older (Figure 2) [27]. Older individuals are more likely to be familiar with the diseases against which vaccines protect, which influences their beliefs. There were no differences in beliefs according to political party affiliation or sex. We have a great deal of educating to do with regard to the risks of diseases and the safety of vaccines in young parents.