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This week at Infection Landscapes I will conclude the 2 part series on measles by examining the measles vaccine, as well as efforts in various areas across the world to control and eliminate the disease. We will take a solid look at good clinical and epidemiologic data showing measles vaccine to be safe and effective in preventiing measles. We will also examine the fraudulent Wakefield study to show how the results and conclusions do not represent good science. I will conclude with a discussion of the potential for measles eradication. As we will see, the nature of the infection has some elements that make it a good candidate for eradication, while other features that present significant, and perhaps, insurmountable obstacles. We inhabit a moment in time demanding sober consideration of measles, because we are, unfortunately, on the brink of widespread epidemic.
The Vaccine. It is beyond the scope of this publication to present a complete introduction to vaccinology. Nevertheless, I think it will be instructive to give some general background on vaccines so that the reader can be grounded in a basic understanding of how they work. Vaccines can be said to fit within 2 broad categories of infection resistance: First, there are those that confer resistance by engaging passive immunity, and second, there are those that confer resistance by engaging active immunity. Vaccines that utilize passive immunity involve the direct injection of non-host antibodies into the host. These vaccines do not involve the host mounting an immune response to antigen. As such, the protection conferred from these kinds of vaccines are typically very short lived. Incidentally, passive immunity is also engaged when maternal antibodies are passed from mother to fetus in utero, and from mother to infant during breastfeeding.
Active immunity, on the other hand, results in protection that is a product of the host's own immune system. Active immunity follows the host's own immune response following exposure to an antigen. Immunogenic antigens are foreign particles, commonly protein or polysaccharide components of organisms, that are recognized by the host's immune system and subsequently elicit a response. Ultimately, the goal of active immunization is to stimulate an immune response to one or more of these antigens, which then confers protective immunity to natural infection by the pathogenic organism without causing serious clinical illness.
Depending on what aspects of a vaccine you are trying to classify, or research, there are four broad categories of vaccines that stimulate active immunity: live attenuated vaccines, inactivated vaccines, recombinant vaccines, and DNA vaccines. The first two are mutually exclusive, since the first involves a living organism and the second does not, but not all four categories are necessarily exclusive of each other. For the sake of simplicity I am going to limit this brief introduction to a description of the first two categories: live attenuated vaccines and inactivated vaccines.
Live attenuated vaccines are vaccines wherein the pathogenic organism has been rendered non-pathogenic, but remains viable. I say "viable" rather than "alive" because viruses cannot be said to be truly alive (to be fair, this is the source of some considerable debate). The essential function of such a vaccine is to inoculate the host with the viable organism, in non-pathogenic form, so that it can replicate or multiply in the host and thereby induce an immune response. The ability of the organism to make more of itself is the critical step, which, of course, requires that the organism remains "alive" even though it is no longer pathogenic. Live vaccines typically generate a strong immune response, stimulating both humoral and cell-mediated immunity, both of which also involve the production of memory B and T cells, respectively. As such, the active immunity gained from live vaccines tends to be long-term, often life-long, if the correct dosing schedule is followed. While these vaccines are very good at stimulating powerful immune responses and conferring long-term immune memmory, their widespread distribution can often be hampered by one important factor: they require a cold chain. Because the organisms in the vaccines are viable "living" organisms, they require a regulated microclimate during the course of their transportation from one geographical area to the next. In other words, they have to be kept at a constant temperature, which is typically much cooler than the outdoor temperature in tropical locations. Thus, the geographic distribution of live vaccines requires that they be kept "cold" at each point along the transport "chain" as they move by air, road, waterway, or cross-country, through the landscape. Thus, the cold chain. In tropical or sub-tropical resource-poor areas this can be a daunting logistical task, which often foils attempts at widespread distribution of vaccine.
Inactivated vaccines consist of either 1) whole microbes that have been "killed", using heat or chemicals, for example, or 2) extracted or purified components of the organisms, which serve as immunogenic antigens to stimulate the host's immune response. Inactivated vaccines typically stimulate short-lived immunity that is more humoral than cell-mediated, and which is much poorer at generating immunologic memory. This is because the organisms are no longer viable and so do not replicate in the host. These vaccines will often require several doses to boost the specific antibody level, and since the immunologic memory produced is not good, the protective immunity conferred usually wanes with time, which necessitates booster doses to reestablish immunity. One of the great benefits of inactivated vaccines, however, is their robustness to the environment. Because they do not incorporate viable organisms, these vaccines typically do not require a cold chain. As such, they are much more amenable to widespread distribution in geographic locations that would otherwise present logistical difficulties in dissemination.
This very brief introduction just scratches the surface of vaccines. In the infectious disease course that I teach, I usually spend 2 lectures on general vaccinology. Nevertheless, the current description should provide a basic understanding of the nature of vaccines so that we can proceed to discuss the measles vaccine specifically.
Measles vaccine is a live attenuated vaccine. It can be administered as a single-antigen vaccine for measles virus alone, or it can be combined with other antigen innoculations for combination vaccination programs. Examples of the latter include the measles-rubella (MR) vaccine, the measles-mumps-rubella (MMR) vaccine, or the measles-mumps-rubella-varicella (MMRV) vaccine. The vaccine, in each of these forms, is remarkably effective at conferring individual protection and herd immunity, when administration is optimized. Optimal administration of measles vaccine is determined by three critical factors: First, the age at which the first dose of vaccine is given; Second, the scheduling of second, follow-up inoculations in routine vaccine schedules; Third, the level of vaccine coverage across the whole population.
Let's consider each in turn.
The age at which children received their first vaccination is directly associated with the success of the vaccine. Administering the vaccine at 9 months of age, which is the age of routine vaccination in many countries where measles is endemic, will typically result in approximately 85% of the children developing protective antibody titers. However, when the vaccine is administered at 12 months of age, between 90% and 95% of children develop protective antibody titers. The difference is due to the cross-reaction of the vaccine with maternal antibodies, which may still be circulating in large enough quantities in some children to prevent the immune system from mounting a complete immune response to the attenuated measles virus. As such, the vaccine can lose its efficacy in up to 10% of children. However, as we discussed in detail in Measles Part 1, in countries where measles is endemic, the administration of vaccine at an earlier age may be a public health necessity in order to prevent maximal morbidity and mortality in the most vulnerable population, i.e. young children and infants. Therefore, it will often be the case, that a large-scale measles control campaign will first have to prioritize a shift in the burden of disease from the youngest children to the older children, so the age-dynamics of measles transmission will also shift. Such a shift will eventually lead to less risk in the youngest age group, and thus the ability to vaccinate at 12 months instead of 9 months, with the resulting improved efficacy and increased generalized herd immunity soon to follow. See Measles Part 1 for an explanation of measles transmission dynamics.
The scheduling of second inoculations as part of routine vaccination schedules is very important because the duration of protection conferred by measles vaccine will not be life-long for everyone inoculated. In fact, secondary vaccine failure occurs in approximately 5% of children between 10 and 15 years after the initial vaccination. This may not sound like much, but in most populations it will be enough to compromise herd immunity and in any population it will always be enough to interrupt the potential for virus elimination. This is due to the extreme infectivity of measles virus as discussed last time in Measles Part 1.
The level of vaccine coverage across a given population is an important contributor to the endemicity of disease and the transmission dynamics, which, again, where described in detail in Measles Part 1. A minimum of 95% consistent vaccine coverage in a population is required to both maintain complete herd immunity and create the potential for measles elimination in that population. This high level of vaccine coverage is, again, due to the highly infectious nature of the measles virus.
In summary, across decades of rigorous study we know the following: approximately 5-15% of vaccine recipients will develop fever following vaccination. Also, approximately 5% of vaccine recipients will develop a transient rash that resolves in a few days. There is NO association, causal or otherwise, between measles vaccine and autism.
In addition to decades of scientific research that has unequivocally established the safety and effectiveness of measles vaccine, In the United States there are 2 very important surveillance programs in place, which are responsible for collecting data on all adverse events associated with all vaccine administration across the country on an annual basis. And these programs will continue to do so for as long as we administer vaccines. The first program is the Vaccine Safety Datalink (VSD), which was established in 1991 as a partnership between the Centers for Disease Control and Prevention (CDC) and health management organizations (HMOs). This program has effectively established large age cohorts over the last 20 years for the observation of any potential adverse events associated with any vaccine administered in the HMO setting, which constitutes the majority of personal interface with clinical services in the United States. While initially established for children, this vaccine surveillance program has subsequently been expanded to include adolescents and adults as well.
The other major program is the National Vaccine Adverse Events Reporting System (VAERS). This is a passive surveillance system so it is dependent upon the accurate reporting of clinical personnel and local health departments for the collection of case-series data. Unlike the VSD, the VAERS results are based on case-series so there is no denominator and, thus, this surveillance system cannot be used to estimate rates. As such, VAERS is primarily an early warning system for identifying adverse or rare events associated with vaccines, whereas the VSD is used for estimating rates.
The combination of decades of sound, peer-reviewed scientific research with long-term national surveillance programs have provided overwhelming evidence that measles vaccine is remarkably safe and effective. As I said before, this is not an opinion but rather a scientifically drawn conclusion based on long-term and substantive data. Even still, broad surveillance systems are in place and are well established so that all vaccines are meticulously monitored in the actual human populations in which they are administered. Measles vaccination is safe. We are protected, if we vaccinate.
History and Successes of Vaccination Campaigns. We have discussed how vaccines work, in general, and the nature of measles vaccine, in particular. We have discussed the evidence of measles vaccine safety and efficacy. Now, let us examine the history of measles vaccine intervention and explore the population-based effectiveness of vaccine program implementation, and the great strides that have been made toward control and elimination of this deadly disease.
The measles vaccine was introduced in the United States in 1963 as a single antigen, single dose vaccine. The combination MMR vaccine replaced the single antigen vaccine in 1971, and the two dose schedule was implemented in 1989. Before widespread implementation of the measles vaccine in 1963, there were approximately 500,000 cases of measles per year in the United States. The initial, single dose program reduced measles incidence to approximately 20,000 cases per year by 1968, an already impressive 25-fold reduction in disease. Nevertheless, it was quickly recognized that a single dose across the life course would still leave roughly 5% of the population without immunity due to the 5% vaccine failure after the first inoculation. A second inoculation was shown to be efficacious in 95% of the 5% who had secondary vaccine failure following the first inoculation. A such, the suggested vaccine schedule was expanded to the following in 1989: first dose at 12 to 15 months of age, followed by the second dose at 4 to 6 years of age (corresponding to the time when children enter school). Following the widespread adoption of the expanded schedule, measles incidence was reduced to less than 150 cases per year from 1997 through 2005. The national low was 37 cases in 2004. Here is an informative graph from the CDC demonstrating the change in measles incidence from 1944 to 2007 and how this trajectory is coincident with the introduction of the single and two dose vaccine schedules:
Success has not been limited to the United States, however. Indeed, effective control has been far more widespread throughout the western hemisphere largely due to extraordinary efforts by the Pan American Health Organization (PAHO). By 2002, autochthonous measles was declared eliminated in the western hemisphere. Measles was gone from the Americas with only minor isolated loci of endemicity in the far northern provinces of arctic Canada. While the United States had the benefit of large-scale resources in terms of vaccine production and administration infrastructure, most of the rest of the Americas did not. PAHO's massive mobilization of vaccination campaigns across many diverse local populations throughout the Americas represents one of the most successful public health accomplishments in human history. The PAHO campaign was (and is) comprised of four essential components of vaccination implementation that proceed in distinct phases: Catch-up, Keep-up, Follow-up, and Mop-up.
Catch-up: This is the first phase of the program utilizing a brute force, all-out approach to begin the process of measles elimination. It is a one-time, population-wide comprehensive vaccination of all children between the ages of 1 to 14 years regardless of previous vaccination or disease history.
Keep-up: Although this is the second phase, it also begins at the inception of the overall program. This phase is focused on improving the ongoing regular vaccination program that follows a specific schedule for every individual in a population, beginning in infancy. For example, in the United States, the regular vaccination schedule requires immunization for all children at 12-15 months of age, and then again at 4-6 years of age. This is part of the regular public health infrastructure. So, the object of this phase of the PAHO program was simply to improve the public health infrastructure such that all new children born into a population receive vaccination once they reach the appropriate vaccination age. The specific PAHO goal for this phase has been to achieve 90% regular vaccination coverage in each successive birth cohort.
Follow-up: This phase consists of subsequent, intermittent, population-wide mass vaccination campaigns every 3 to 5 years that now target all children between the ages of 1 to 5 years, but again regardless of previous vaccine or disease history.
Mop-up: This final phases consists of regular ongoing targeting of special, particularly difficult to reach, subpopulations within the wider community. An example of uniquely targeted groups in the Mop-up phase are the homeless, displaced communities, and migratory peoples in difficult to reach geographies.
In addition to these four phases of the broader campaign, measles surveillance with laboratory confirmation of all reported cases has been implemented in every country in the western hemisphere.
The results of this extraordinary campaign are dramatic. Measles incidence has been reduced across the whole of the Americas by greater than 99%, from greater than 250,000 cases per year in 1990 to only 85 cases in 2005. Below is a report from the CDC's Morbidity and Mortality Weekly Report on the early success of the PAHO campaign (published here):
This PAHO campaign is now the global model for regional elimination of measles across the greatly varied geographic landscapes wherein endemic measles remains a credible threat to child health.
In the broader global arena, however, the scope will not necessarily be the same in all geographic regions. This is primarily due to the availability of resources.
Here is the global distribution of vaccine coverage according to the World Health Organization in 2007:
There clearly remains a deficit in coverage for much of Africa and Southeast Asia. There are two factors that conspire to make measles elimination in these regions especially difficult. The first is the nature of the virus, itself, and its extremely high infectivity as we discussed in Measles Part 1. The infectious quality of the virus requires that approximately 95% vaccine coverage is attained in order to hold realistic prospects for regional elimination of measles. The nature of the vaccine is the second important factor that, along with the highly infectious pathogen, undermines efforts to achieve high vaccine coverage: it is a live-attenuated vaccine. Thus it requires a cold chain. The logistics of cold chain transport can be quite challenging in many of the rural areas in the countries represented in the map above. Logistical difficulties are compounded by poverty. Poor countries often lack the resources to obtain enough vaccine for distribution to the whole population, as well as maintaining a cold chain across the large network of transport required to administer the vaccine to all children in the population.
As such, attempts at measles control, especially in resource poor areas, with geographically semi-isolated communities, may begin with goals of mortality reduction rather than regional elimination. The Global Immunization Vision and Strategy (GIVS), which was conceptualized by the a joint effort of the WHO and UNICEF. This strategy calls on UN member states to reduce measles mortality by 90% from that which was experienced in 2000. Mortality reduction campaigns typically employ a one-time, population-wide mass vaccination campaign targeting all children around the age of 9 months. Reducing mortality first may be the most viable first step for measles control in those parts of the world where the disease endemicity remains high.
In addition, some areas where measles elimination had been realized are now threatened with resurgent disease due to waning adherence to vaccine schedules. Much of this lack of adherence stems from public misunderstanding due to the reporting of the flawed study described above. Tens of thousands of cases of measles now occur annually in the UK and France alone. While less in the United States, we nevertheless experienced three times the normal incidence of measles here by the first half of 2011.
The irony is that measles virus is a good candidate for complete eradication, as was achieved with smallpox. Here's why: 1) it has no reservoir other than humans, thus preventing the virus' survival in any sylvan disease cycle, 2) despite being an RNA virus, the RNA genome of measles virus has a fairly low rate of mutation over time, which means we do not have to worry about constantly creating new vaccines in response to antigenic drift, and 3) the vaccine confers a high level of immunogenicity in the host.
However, there is one factor, as described above, that may forever undermine attempts at eradication: the measles virus is so infectious that it requires vaccination of 95% of a given population to effect elimination in that population. Given the difficulty of vaccine transport in those areas where endemicity remains greatest, we find ourselves so close...and, yet, so far.
This week at Infection Landscapes I will conclude the 2 part series on measles by examining the measles vaccine, as well as efforts in various areas across the world to control and eliminate the disease. We will take a solid look at good clinical and epidemiologic data showing measles vaccine to be safe and effective in preventiing measles. We will also examine the fraudulent Wakefield study to show how the results and conclusions do not represent good science. I will conclude with a discussion of the potential for measles eradication. As we will see, the nature of the infection has some elements that make it a good candidate for eradication, while other features that present significant, and perhaps, insurmountable obstacles. We inhabit a moment in time demanding sober consideration of measles, because we are, unfortunately, on the brink of widespread epidemic.
The Vaccine. It is beyond the scope of this publication to present a complete introduction to vaccinology. Nevertheless, I think it will be instructive to give some general background on vaccines so that the reader can be grounded in a basic understanding of how they work. Vaccines can be said to fit within 2 broad categories of infection resistance: First, there are those that confer resistance by engaging passive immunity, and second, there are those that confer resistance by engaging active immunity. Vaccines that utilize passive immunity involve the direct injection of non-host antibodies into the host. These vaccines do not involve the host mounting an immune response to antigen. As such, the protection conferred from these kinds of vaccines are typically very short lived. Incidentally, passive immunity is also engaged when maternal antibodies are passed from mother to fetus in utero, and from mother to infant during breastfeeding.
Active immunity, on the other hand, results in protection that is a product of the host's own immune system. Active immunity follows the host's own immune response following exposure to an antigen. Immunogenic antigens are foreign particles, commonly protein or polysaccharide components of organisms, that are recognized by the host's immune system and subsequently elicit a response. Ultimately, the goal of active immunization is to stimulate an immune response to one or more of these antigens, which then confers protective immunity to natural infection by the pathogenic organism without causing serious clinical illness.
Depending on what aspects of a vaccine you are trying to classify, or research, there are four broad categories of vaccines that stimulate active immunity: live attenuated vaccines, inactivated vaccines, recombinant vaccines, and DNA vaccines. The first two are mutually exclusive, since the first involves a living organism and the second does not, but not all four categories are necessarily exclusive of each other. For the sake of simplicity I am going to limit this brief introduction to a description of the first two categories: live attenuated vaccines and inactivated vaccines.
Live attenuated vaccines are vaccines wherein the pathogenic organism has been rendered non-pathogenic, but remains viable. I say "viable" rather than "alive" because viruses cannot be said to be truly alive (to be fair, this is the source of some considerable debate). The essential function of such a vaccine is to inoculate the host with the viable organism, in non-pathogenic form, so that it can replicate or multiply in the host and thereby induce an immune response. The ability of the organism to make more of itself is the critical step, which, of course, requires that the organism remains "alive" even though it is no longer pathogenic. Live vaccines typically generate a strong immune response, stimulating both humoral and cell-mediated immunity, both of which also involve the production of memory B and T cells, respectively. As such, the active immunity gained from live vaccines tends to be long-term, often life-long, if the correct dosing schedule is followed. While these vaccines are very good at stimulating powerful immune responses and conferring long-term immune memmory, their widespread distribution can often be hampered by one important factor: they require a cold chain. Because the organisms in the vaccines are viable "living" organisms, they require a regulated microclimate during the course of their transportation from one geographical area to the next. In other words, they have to be kept at a constant temperature, which is typically much cooler than the outdoor temperature in tropical locations. Thus, the geographic distribution of live vaccines requires that they be kept "cold" at each point along the transport "chain" as they move by air, road, waterway, or cross-country, through the landscape. Thus, the cold chain. In tropical or sub-tropical resource-poor areas this can be a daunting logistical task, which often foils attempts at widespread distribution of vaccine.
Inactivated vaccines consist of either 1) whole microbes that have been "killed", using heat or chemicals, for example, or 2) extracted or purified components of the organisms, which serve as immunogenic antigens to stimulate the host's immune response. Inactivated vaccines typically stimulate short-lived immunity that is more humoral than cell-mediated, and which is much poorer at generating immunologic memory. This is because the organisms are no longer viable and so do not replicate in the host. These vaccines will often require several doses to boost the specific antibody level, and since the immunologic memory produced is not good, the protective immunity conferred usually wanes with time, which necessitates booster doses to reestablish immunity. One of the great benefits of inactivated vaccines, however, is their robustness to the environment. Because they do not incorporate viable organisms, these vaccines typically do not require a cold chain. As such, they are much more amenable to widespread distribution in geographic locations that would otherwise present logistical difficulties in dissemination.
This very brief introduction just scratches the surface of vaccines. In the infectious disease course that I teach, I usually spend 2 lectures on general vaccinology. Nevertheless, the current description should provide a basic understanding of the nature of vaccines so that we can proceed to discuss the measles vaccine specifically.
Measles vaccine is a live attenuated vaccine. It can be administered as a single-antigen vaccine for measles virus alone, or it can be combined with other antigen innoculations for combination vaccination programs. Examples of the latter include the measles-rubella (MR) vaccine, the measles-mumps-rubella (MMR) vaccine, or the measles-mumps-rubella-varicella (MMRV) vaccine. The vaccine, in each of these forms, is remarkably effective at conferring individual protection and herd immunity, when administration is optimized. Optimal administration of measles vaccine is determined by three critical factors: First, the age at which the first dose of vaccine is given; Second, the scheduling of second, follow-up inoculations in routine vaccine schedules; Third, the level of vaccine coverage across the whole population.
Let's consider each in turn.
The age at which children received their first vaccination is directly associated with the success of the vaccine. Administering the vaccine at 9 months of age, which is the age of routine vaccination in many countries where measles is endemic, will typically result in approximately 85% of the children developing protective antibody titers. However, when the vaccine is administered at 12 months of age, between 90% and 95% of children develop protective antibody titers. The difference is due to the cross-reaction of the vaccine with maternal antibodies, which may still be circulating in large enough quantities in some children to prevent the immune system from mounting a complete immune response to the attenuated measles virus. As such, the vaccine can lose its efficacy in up to 10% of children. However, as we discussed in detail in Measles Part 1, in countries where measles is endemic, the administration of vaccine at an earlier age may be a public health necessity in order to prevent maximal morbidity and mortality in the most vulnerable population, i.e. young children and infants. Therefore, it will often be the case, that a large-scale measles control campaign will first have to prioritize a shift in the burden of disease from the youngest children to the older children, so the age-dynamics of measles transmission will also shift. Such a shift will eventually lead to less risk in the youngest age group, and thus the ability to vaccinate at 12 months instead of 9 months, with the resulting improved efficacy and increased generalized herd immunity soon to follow. See Measles Part 1 for an explanation of measles transmission dynamics.
The scheduling of second inoculations as part of routine vaccination schedules is very important because the duration of protection conferred by measles vaccine will not be life-long for everyone inoculated. In fact, secondary vaccine failure occurs in approximately 5% of children between 10 and 15 years after the initial vaccination. This may not sound like much, but in most populations it will be enough to compromise herd immunity and in any population it will always be enough to interrupt the potential for virus elimination. This is due to the extreme infectivity of measles virus as discussed last time in Measles Part 1.
The level of vaccine coverage across a given population is an important contributor to the endemicity of disease and the transmission dynamics, which, again, where described in detail in Measles Part 1. A minimum of 95% consistent vaccine coverage in a population is required to both maintain complete herd immunity and create the potential for measles elimination in that population. This high level of vaccine coverage is, again, due to the highly infectious nature of the measles virus.
Are there adverse events associated with this vaccine? Let's consider the reality: To begin, this vaccine, as I have already stated above, is very safe. This is not my opinion, nor is it the opinion of the public health or medical community. Instead, this is a conclusion drawn from extensive and exhaustive study conducted over 50 years, from the early 1960s (the vaccine was introduced in 1963) until the present day. In March 1968, a study was published in the British Medical Journal comparing the administration of live measles vaccine, live plus killed measles vaccine, and no vaccine among 36, 211 British children randomized to one of the three arms. This publication constituted the Second Report to the Medical Research Council by the Measles Vaccines Committee of the UK. The study was initiated in 1964 and reported on two years of follow-up in this population sample. The live vaccine alone showed 94%, and the live plus killed vaccine showed 88% efficacy, and neither demonstrated any complications. This study represents some of the earliest population-based, randomized controlled trial data we have with very large numbers of participants. It is a very good early argument for the efficacy and safety of measles vaccine. Many subsequent studies followed reaffirming these findings.
Today, however, the trivalent measles, mumps, rubella (MMR) vaccine is the form common to most vaccine schedules. In 1975, the Bullentin of the World Health Organization reported the results from a population-based randomized controlled trial in the Dominican Republic. Immunogenicity was achieved in 99% of the 926 participants. Furthermore, there was no difference in side effects between the trivalent vaccinees and those receiving either the monovalent measles vaccine, or no vaccine at all. Similarly, this report represents some of the earliest population-based randomized controlled trial data demonstrating the safety and efficacy of the MMR vaccine.
These early studies have been followed by decades of similar studies affirming the safety and efficacy of measles vaccination. An exhaustive systematic review was conducted by the European Research Program for Improved Vaccine Safety Surveillance. This review, which was published in the journal Vaccine in September of 2003, examined 22 high-quality prospective and retrospective studies conducted to assess potential adverse events associated with MMR. Synthesizing all of these studies, the report concluded that the MMR is not associated with Crohn's disease, autism, asceptic meningitis, or other major adverse events when comparing vaccinees to placebo.
These early studies have been followed by decades of similar studies affirming the safety and efficacy of measles vaccination. An exhaustive systematic review was conducted by the European Research Program for Improved Vaccine Safety Surveillance. This review, which was published in the journal Vaccine in September of 2003, examined 22 high-quality prospective and retrospective studies conducted to assess potential adverse events associated with MMR. Synthesizing all of these studies, the report concluded that the MMR is not associated with Crohn's disease, autism, asceptic meningitis, or other major adverse events when comparing vaccinees to placebo.
In February of 1998, the Lancet published a study by Andrew Wakefield and colleagues entitled, Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. This paper, which has now been retracted by the Lancet because the methods, data and conduct of the study have been thoroughly discredited, posited an assoication between reciept of the MMR vaccine and the development of autism. This claim was based on 12 gastrointestinal patients of the author. The authors purported that the MMR vaccine components caused inflammation in the epithelium of the gut tract in these children, which subsequently led to neurologic sequelae consistent with autism. This study had no control group, and no biologic plausibility defined by a pathway from MMR inoculation to gut disease to autism. No such relationships had previously be reported, nor was there any biologic model in which they fit. In addition, the temporal association between MMR vaccine and gut and neurologic symptoms was based on retrospective assessment of vaccine history by the parents. Thus, there is great potential for recall bias. So the conclusions based on the data, as they were, were not scientifically sound. Moreover, it has since been revealed, largely due to the outstanding investigation conducted by Brian Deer for the the Times of London, that, aside from the scientifically unsound conclusions drawn from the paper's results, Wakefield falsified the actual laboratory findings, which found no MMR DNA sequences in 99% of the samples tested. Those that were positive were not different among the autistic and non-autistic children. Furthermore, Deer's investigations revealed several conflicts of interest, including a patent for a new monovalent measles vaccine and over half a million pounds in funding from a legal firm to aid in identifying a link between MMR and autism.
During the initial press conference convened to adress Wakefield's 1998 Lancet paper, he stated that he did not think it safe to continue with trivalent vaccination against measles, mumps and rubella until the link between MMR and autism could be more clearly elucidated. This media coverage, as well as the explosive media coverage that followed for several years, is likely responsible for the dramatic decline in MMR vaccination in the beginning of the 21st century and the subsequent rise in measles incidence in many countries that had previously attained very good levels of measles control. Many thousands of cases and hundreds of deaths have followed in geographic regions where measles had been eliminated.
Andrew Wakefield's unethical and fraudulent scientific conduct notwithstanding, there have been a plethora of well conducted epidemiologc studies examining the potential association between autism and MMR, autism and thimerosal, and autism and multiple vaccine administration. All have shown that no association exists between autism and vaccination. In February of 2009, the journal Vaccine published another a review of 27 studies examining each of these possible links, all of which were clearly shown to demonstrate no association with autism.
In addition to decades of scientific research that has unequivocally established the safety and effectiveness of measles vaccine, In the United States there are 2 very important surveillance programs in place, which are responsible for collecting data on all adverse events associated with all vaccine administration across the country on an annual basis. And these programs will continue to do so for as long as we administer vaccines. The first program is the Vaccine Safety Datalink (VSD), which was established in 1991 as a partnership between the Centers for Disease Control and Prevention (CDC) and health management organizations (HMOs). This program has effectively established large age cohorts over the last 20 years for the observation of any potential adverse events associated with any vaccine administered in the HMO setting, which constitutes the majority of personal interface with clinical services in the United States. While initially established for children, this vaccine surveillance program has subsequently been expanded to include adolescents and adults as well.
The other major program is the National Vaccine Adverse Events Reporting System (VAERS). This is a passive surveillance system so it is dependent upon the accurate reporting of clinical personnel and local health departments for the collection of case-series data. Unlike the VSD, the VAERS results are based on case-series so there is no denominator and, thus, this surveillance system cannot be used to estimate rates. As such, VAERS is primarily an early warning system for identifying adverse or rare events associated with vaccines, whereas the VSD is used for estimating rates.
The combination of decades of sound, peer-reviewed scientific research with long-term national surveillance programs have provided overwhelming evidence that measles vaccine is remarkably safe and effective. As I said before, this is not an opinion but rather a scientifically drawn conclusion based on long-term and substantive data. Even still, broad surveillance systems are in place and are well established so that all vaccines are meticulously monitored in the actual human populations in which they are administered. Measles vaccination is safe. We are protected, if we vaccinate.
History and Successes of Vaccination Campaigns. We have discussed how vaccines work, in general, and the nature of measles vaccine, in particular. We have discussed the evidence of measles vaccine safety and efficacy. Now, let us examine the history of measles vaccine intervention and explore the population-based effectiveness of vaccine program implementation, and the great strides that have been made toward control and elimination of this deadly disease.
The measles vaccine was introduced in the United States in 1963 as a single antigen, single dose vaccine. The combination MMR vaccine replaced the single antigen vaccine in 1971, and the two dose schedule was implemented in 1989. Before widespread implementation of the measles vaccine in 1963, there were approximately 500,000 cases of measles per year in the United States. The initial, single dose program reduced measles incidence to approximately 20,000 cases per year by 1968, an already impressive 25-fold reduction in disease. Nevertheless, it was quickly recognized that a single dose across the life course would still leave roughly 5% of the population without immunity due to the 5% vaccine failure after the first inoculation. A second inoculation was shown to be efficacious in 95% of the 5% who had secondary vaccine failure following the first inoculation. A such, the suggested vaccine schedule was expanded to the following in 1989: first dose at 12 to 15 months of age, followed by the second dose at 4 to 6 years of age (corresponding to the time when children enter school). Following the widespread adoption of the expanded schedule, measles incidence was reduced to less than 150 cases per year from 1997 through 2005. The national low was 37 cases in 2004. Here is an informative graph from the CDC demonstrating the change in measles incidence from 1944 to 2007 and how this trajectory is coincident with the introduction of the single and two dose vaccine schedules:
Success has not been limited to the United States, however. Indeed, effective control has been far more widespread throughout the western hemisphere largely due to extraordinary efforts by the Pan American Health Organization (PAHO). By 2002, autochthonous measles was declared eliminated in the western hemisphere. Measles was gone from the Americas with only minor isolated loci of endemicity in the far northern provinces of arctic Canada. While the United States had the benefit of large-scale resources in terms of vaccine production and administration infrastructure, most of the rest of the Americas did not. PAHO's massive mobilization of vaccination campaigns across many diverse local populations throughout the Americas represents one of the most successful public health accomplishments in human history. The PAHO campaign was (and is) comprised of four essential components of vaccination implementation that proceed in distinct phases: Catch-up, Keep-up, Follow-up, and Mop-up.
Catch-up: This is the first phase of the program utilizing a brute force, all-out approach to begin the process of measles elimination. It is a one-time, population-wide comprehensive vaccination of all children between the ages of 1 to 14 years regardless of previous vaccination or disease history.
Keep-up: Although this is the second phase, it also begins at the inception of the overall program. This phase is focused on improving the ongoing regular vaccination program that follows a specific schedule for every individual in a population, beginning in infancy. For example, in the United States, the regular vaccination schedule requires immunization for all children at 12-15 months of age, and then again at 4-6 years of age. This is part of the regular public health infrastructure. So, the object of this phase of the PAHO program was simply to improve the public health infrastructure such that all new children born into a population receive vaccination once they reach the appropriate vaccination age. The specific PAHO goal for this phase has been to achieve 90% regular vaccination coverage in each successive birth cohort.
Follow-up: This phase consists of subsequent, intermittent, population-wide mass vaccination campaigns every 3 to 5 years that now target all children between the ages of 1 to 5 years, but again regardless of previous vaccine or disease history.
Mop-up: This final phases consists of regular ongoing targeting of special, particularly difficult to reach, subpopulations within the wider community. An example of uniquely targeted groups in the Mop-up phase are the homeless, displaced communities, and migratory peoples in difficult to reach geographies.
In addition to these four phases of the broader campaign, measles surveillance with laboratory confirmation of all reported cases has been implemented in every country in the western hemisphere.
The results of this extraordinary campaign are dramatic. Measles incidence has been reduced across the whole of the Americas by greater than 99%, from greater than 250,000 cases per year in 1990 to only 85 cases in 2005. Below is a report from the CDC's Morbidity and Mortality Weekly Report on the early success of the PAHO campaign (published here):
This PAHO campaign is now the global model for regional elimination of measles across the greatly varied geographic landscapes wherein endemic measles remains a credible threat to child health.
In the broader global arena, however, the scope will not necessarily be the same in all geographic regions. This is primarily due to the availability of resources.
Here is the global distribution of vaccine coverage according to the World Health Organization in 2007:
There clearly remains a deficit in coverage for much of Africa and Southeast Asia. There are two factors that conspire to make measles elimination in these regions especially difficult. The first is the nature of the virus, itself, and its extremely high infectivity as we discussed in Measles Part 1. The infectious quality of the virus requires that approximately 95% vaccine coverage is attained in order to hold realistic prospects for regional elimination of measles. The nature of the vaccine is the second important factor that, along with the highly infectious pathogen, undermines efforts to achieve high vaccine coverage: it is a live-attenuated vaccine. Thus it requires a cold chain. The logistics of cold chain transport can be quite challenging in many of the rural areas in the countries represented in the map above. Logistical difficulties are compounded by poverty. Poor countries often lack the resources to obtain enough vaccine for distribution to the whole population, as well as maintaining a cold chain across the large network of transport required to administer the vaccine to all children in the population.
As such, attempts at measles control, especially in resource poor areas, with geographically semi-isolated communities, may begin with goals of mortality reduction rather than regional elimination. The Global Immunization Vision and Strategy (GIVS), which was conceptualized by the a joint effort of the WHO and UNICEF. This strategy calls on UN member states to reduce measles mortality by 90% from that which was experienced in 2000. Mortality reduction campaigns typically employ a one-time, population-wide mass vaccination campaign targeting all children around the age of 9 months. Reducing mortality first may be the most viable first step for measles control in those parts of the world where the disease endemicity remains high.
In addition, some areas where measles elimination had been realized are now threatened with resurgent disease due to waning adherence to vaccine schedules. Much of this lack of adherence stems from public misunderstanding due to the reporting of the flawed study described above. Tens of thousands of cases of measles now occur annually in the UK and France alone. While less in the United States, we nevertheless experienced three times the normal incidence of measles here by the first half of 2011.
The irony is that measles virus is a good candidate for complete eradication, as was achieved with smallpox. Here's why: 1) it has no reservoir other than humans, thus preventing the virus' survival in any sylvan disease cycle, 2) despite being an RNA virus, the RNA genome of measles virus has a fairly low rate of mutation over time, which means we do not have to worry about constantly creating new vaccines in response to antigenic drift, and 3) the vaccine confers a high level of immunogenicity in the host.
However, there is one factor, as described above, that may forever undermine attempts at eradication: the measles virus is so infectious that it requires vaccination of 95% of a given population to effect elimination in that population. Given the difficulty of vaccine transport in those areas where endemicity remains greatest, we find ourselves so close...and, yet, so far.