5: Surveillance for Vaccine-Preventable Diseases and Immunization

Surveillance for Vaccine-Preventable Diseases and Immunization

Daniel C. Payne

Centers for Disease Control and Prevention, Atlanta, GA, USA

Introduction

Vaccine-preventable disease (VPD) surveillance is grounded in a firm understanding of the pathogenesis, clinical course, epidemiological risk factors, and molecular characterization of the disease agent targeted for vaccination. Therefore, VPD surveillance begins well before the vaccine is even developed, approved, and widely administered. The clinical, epidemiological, and laboratory characteristics of the disease agent are the foundations for developing valid, scientifically accurate assessments of the VPD in populations during the widespread use of the vaccine.

Critical functions of VPD surveillance activities are those that evaluate vaccine policy, including understanding pathogen epidemiology, vaccine impact, vaccine coverage, safety, and effectiveness. A lab component could monitor for molecular changes, whether influenced by the vaccination program (e.g., when the pathogen genetically adapts to post-vaccine selective pressures) or not (e.g., through antigenic drift). Continued monitoring over time is important and may lead to unexpected findings. Communicating these results through peer-reviewed publications, scientific conferences and symposiums, reports to governmental and industry oversight boards, domestic and international networks, and healthcare providers ensures that the scientific and regulatory communities accumulate a common knowledge of these findings, and can therefore tailor assessments and recommendations appropriately.

In this chapter, we will describe the factors required for understanding VPD and the lessons learned from previous studies. Then, we will review the components of a thorough VPD surveillance portfolio, and learn the importance of continued monitoring and communication of findings. For these objectives, we will use the example of the U.S. rotavirus vaccination program.

Step One: Understanding the Background: Burden and Risk Factors of VPD Illness and Transmission Processes of the Target Pathogen

An accurate quantitation of the burden of rotavirus illness represents more than simply an introduction to this particular pathogen. These “burden of disease” estimates are the scientific results that led to the understanding that this pathogen contributes substantially to childhood mortality and morbidity and impacts healthcare systems worldwide. Pre-vaccine era epidemiologic data formed the basis for creating meaningful surveillance systems that would come to fruition years later, when vaccines would be developed and introduced, and that would enable public health communities to assess the performance and impact of vaccines upon this VPD.

During the pre-vaccine era, rotavirus infected nearly every unvaccinated child before their fifth birthday. In the absence of vaccine, multiple rotavirus infections may occur during infancy and childhood. Rotavirus causes severe diarrhea and vomiting (acute gastroenteritis [AGE]), which can lead to dehydration, electrolyte depletion, complications of viremia, shock, and death. Nearly one-half million children around the world die of rotavirus infections each year, meaning that it is a significant source of mortality and morbidity among children globally [1].

Even in the United States and other developed countries, where rotavirus infections were much less likely to cause death, this virus was responsible for 40–50% of hospitalizations because of acute gastroenteritis during the winter months in the era before vaccines were introduced. Hundreds of thousands of emergency department (ED) and outpatient visits were a result of rotavirus as well, costing approximately $1 billion each year [2].

Meticulous studies describing how the virus infects humans and observations of when the most severe infections occurred were keys to determining when and how an effective vaccine would be developed and introduced. First rotavirus infections are most likely to result in moderate–severe cases of rotavirus gastroenteritis but subsequent infections are progressively milder. Velazquez et al. [3] found that the adjusted efficacy of a child’s first natural rotavirus infection in protecting against subsequent natural rotavirus-associated diarrhea was 77%. This protection increased to 83% after two natural infections and to 92% after three natural infections. A 3-year study compared rotavirus-infected neonates with uninfected neonates. A similar proportion of neonatally infected and uninfected infants had rotavirus infections during the follow-up period. Symptoms among those neonatally infected, however, were less frequent and less severe leading to the conclusion that neonatal rotavirus infection protects against clinically severe disease during reinfection [4]. A similar finding was reported among a sample of Indian neonates infected in healthcare settings, most of whom had asymptomatic infections, resulting in a protective effect against rotavirus gastroenteritis lasting throughout the 2-year follow-up period, with protection concentrated in the first year of life [5].

The rationale for developing and implementing a vaccination program against rotavirus derived from observations that control measures, such as clean-water initiatives and improvements to personal hygiene, led to dramatic declines in bacterial and parasitic gastroenteritis infections across the world, but rates of rotavirus infection and illness among children in industrialized and less-developed countries remained similar [6–11]. Hygienic measures were unlikely to lead to corresponding declines in rotavirus burden [12]. Because first infections have been shown to induce strong immunity against severe rotavirus reinfections [3] and because vaccination mimics such first infections without causing illness, vaccination was identified as the optimal strategy for decreasing the burden associated with severe and fatal rotavirus diarrhea.

Any changes that may be later attributed to vaccination effects require knowledge of the pre-licensure (i.e., baseline) rates and trends in the target disease as a reference. Baseline data gives public health practitioners the grounding needed to quantitate the extent of observations (whether these are changes in hospital stays attributed to the VPD, mortality rates in a given age group, or other relevant measurements) after the vaccine is being used widely and helps delineate whether any post-licensure changes are likely due to the vaccine or are part of another underlying trend. Efforts to obtain baseline data are necessary before a vaccine is licensed and introduced [13].

Through an understanding of these epidemiological dynamics, VPD surveillance systems would later be able to track the correct clinical settings, clinical characteristics, transmission patterns, and the most likely ages of potential severe infections. This data, in turn, allows accurate assessments of the impact and performance of vaccines in childhood populations.

Step Two: Understanding the Vaccines

VPD surveillance activities should be tailored to an understanding of the vaccines to be assessed and the mechanisms of immunologic protection, as well as the studied and approved parameters by which the vaccines are administered.

During the pre-licensure clinical trial studies that are conducted prior to a vaccine’s approval for widespread use, extensive data is collected regarding the vaccine’s performance in controlled environments, its safety, and other factors that may influence when and how the vaccine is administered. These other factors may include assessments of the ideal age for vaccination and how many vaccine doses are needed to induce an acceptable level of immunity. Early phases of clinical trial (Phase II) may even indicate the best anatomic location for an intramuscular vaccine, dose-ranging studies, or whether an adjuvant improves the immunologic response against a particular antigen in the vaccine.

Using our example of rotavirus vaccines, very large pre-licensure clinical trials indicated that rotavirus vaccines are safe and are not associated with severe vaccine adverse events [14–16]. Rotavirus vaccines are orally administered, live-attenuated vaccines designed for infant immunization in order to avoid the most severe rotavirus infections expected to occur in the first months of life. Following licensure by the Food and Drug Administration (FDA), in February, 2006, a pentavalent (five-strain containing) human-bovine reassortant rotavirus vaccine (RotaTeq™, Merck and Co.) was recommended by the U.S. Advisory Committee on Immunization Practices (ACIP) for routine vaccination of U.S. infants with a 3-dose series administered at ages 2, 4, and 6 months [17]. In June 2008, ACIP updated its recommendations to include the use of a monovalent (single-strain) human attenuated rotavirus vaccine (Rotarix™, GlaxoSmithKline Biologicals) as a 2-dose series administered at ages 2 and 4 months [18].

These findings and recommendations brought several implications to the VPD surveillance for these vaccines. Rotavirus vaccines were tested and approved for very specific age ranges in anticipation that this would reduce the likelihood that the vaccines would be associated with a particular vaccine adverse event (intussusception [IS]—a rare telescoping of the intestine that can lead to serious complications and death) that disproportionately occurs at specific ages. So, assessing rotavirus epidemiologic trends and vaccine safety concerns is clearly linked to age at vaccination. Additionally, the approved number of vaccine doses, which differs between the two rotavirus vaccines, should be taken into consideration. Finally, the fact that the vaccine is live attenuated should be considered: This may influence whether vaccine virus is shed by the recipient, if exposure to this shed virus influences indirect protection among children who did not receive vaccine, and whether the vaccine virus undergoes viral reassortment [19].

Step Three: Identify the Data Sources for Disease Surveillance and Their Availability, Strengths, and Weaknesses

Understanding the characteristics of a particular pathogen, the illness it causes, and the qualities of the vaccines are critical to development of accurate and comprehensive VPD surveillance. Equally important is the comprehension of data sources, their availability, potential biases, and what perspectives they could provide into the world of VPD surveillance.

Many VPDs that are uncommon or do not require laboratory confirmation are made nationally notifiable, either before or after vaccine licensure. The Nationally Notifiable Diseases Surveillance System (NNDSS) is a nationwide collaboration that enables all levels of public health (local, state, territorial, federal, international) to share health information to monitor, control, and prevent the occurrence and spread of state-reportable and nationally notifiable infectious and some noninfectious diseases and conditions.The costly and time-consuming process of creating a completely novel surveillance system is prohibitive in most settings. Typically, existing data sources are assessed for their availability and utility in evaluating the impact of vaccines on epidemiologic trends for a particular pathogen. Sometimes, existing data that is routinely collected is used in a different way for the new function of VPD surveillance.

There is no single perfect data source for assessing any VPD. Meaningful surveillance is achieved by the much broader approach of employing diverse datasets. The true impact of a vaccine or the accurate assessment of disease trends in a population is more likely the result of evaluating many datasets having different strengths and weaknesses. Only by understanding these strengths and weaknesses can a public health practitioner give the appropriate consideration to the findings derived from these data.

National inpatient datasets collect hospital data for large numbers of children, providing powerful tools for estimating whether or not changes in the occurrence of a VPD illness have occurred over time. However, these data may be collected for reasons other than VPD surveillance, such as to track healthcare utilization and expenditures over time by a managed-care organization. Therefore, they may not provide the perfect fit to the VPD surveillance and, instead, may provide just one perspective on epidemiologic trends.

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