Association Between Vaccine Refusal and Vaccine-Preventable Diseases – Detailed Study Notes

Overview & Purpose

  • Review article (JAMA, 2016) examines the link between vaccine delay/refusal/exemption and epidemiology of two vaccine-preventable diseases with recent U.S. outbreaks: measles & pertussis.

  • Importance: resurgence/outbreaks despite high overall coverage; need quantitative understanding of risks attributable to intentional non-vaccination.

  • Objective: Systematically summarize published U.S. literature linking vaccine refusal (delay, exemption, intentional non-vaccination) to disease occurrence after

    • Measles elimination (post-January 1, 2000)

    • Pertussis nadir (post-January 1, 1977)

Background: Coverage, Exemptions & Hesitancy

  • 2013 national vaccine coverage in children 19–35 mo:

    • 91.9\% ≥1 dose MMR

    • 83.1\% ≥4 doses DTaP

  • Despite high coverage, nonmedical exemptions (NMEs) have risen for 2 decades.

    • NMEs include religious or personal/philosophical belief waivers.

    • Early rise limited to states with easy personal-belief exemptions; recently also rising in states with moderate difficulty and religious-only exemptions.

  • Outbreak triggers public/political attention (e.g., 2014 Disneyland measles outbreak: 111 cases across 7 U.S. states + Canada/Mexico; ≈50 % unvaccinated, mostly by choice).

Methods (Literature Search Strategy)

Measles

  • PubMed search through Nov 30 2015 using combinations of: “measles”, “vaccinated/unvaccinated”, “outbreak”, “import*”, “MMWR”, limited to U.S., ≥2000.

  • Separate unrestricted search for “measles risk exemption”.

Pertussis

  • PubMed search through Nov 30 2015 for non-overlapping state/community outbreaks after Jan 1 1977 using: “pertussis epidemic/endemic/outbreak/MMWR”.

  • Additional keywords: “pertussis vaccine refusal/exemption/delay/hesitan*/undervaccination/cluster” with no date limit.

Results – Measles

Recent U.S. Epidemiology

  • Vaccine licensed 1963 → dramatic decline; declared eliminated 2000.

  • 2014 spike: 23 outbreaks, 668 U.S. cases (largest post-elimination annual total).

Outbreak Compilation (2000-2015)

  • 18 key reports ➔ 1 416 cases (age 2 wk–84 y; 178 <12 mo).

    • 56.8\% (804) never received measles vaccine.

    • 199 (14.1 %) previously vaccinated.

    • 405 of 574 age-eligible unvaccinated cases (70.6 %; 41.8 % of all cases) held NMEs.

  • Cumulative epidemic curve (18 outbreaks, 145 cases):

    • 111 unvaccinated, 11 unknown, 23 vaccinated.

    • Unvaccinated dominate index & first-generation spread; outbreaks extend ≤5 generations, latest case at 12 wk.

Individual & Community Risk Studies

  • National study 1985-1992:

    • Children with exemptions had 35\times higher measles risk vs fully vaccinated.

    • Resurgence onset ≈1 y earlier among exempted.

    • Modeling: higher local exemption clustering ➔ higher measles incidence even in vaccinated population.

  • Colorado 1987-1998:

    • 22\times higher risk among exempt vs vaccinated; greatest absolute risk in 3–10 y.

    • County exemption rate correlated with county measles incidence.

    • Index/1st-generation cases: 14.5 % exempt vs 7.1 % in later generations.

Results – Pertussis

Recent U.S. Epidemiology & Contributing Factors

  • Whole-cell vaccine widespread 1940s → incidence nadir (1 010 cases, 1976).

  • Acellular vaccine replaces whole-cell in 1990s; Tdap booster licensed 2005.

  • Annual U.S. cases now >10 000 (≥25 000 in each of last 3 yrs).

  • Waning immunity pivotal:

    • Observational data: longer interval since last DTaP/Tdap ➔ higher pertussis risk.

    • Meta-analysis: odds increase 1.33-fold per year post-DTaP.

Outbreak Compilation (1977-2015)

  • 32 non-overlapping reports; 10 609 cases with vaccine status (age 10 d–87 y).

  • Five largest statewide epidemics showed substantial inadequate vaccination:

    • Arizona 1988 (598 age-eligible cases): 33 % <3 DTaP doses.

    • California 2010 (4 415 cases 6 mo–18 y): 45 % under-/un-vaccinated (380 unvaccinated + 1 621 undervaccinated).

    • Washington 2012 (1 829 cases 3 mo–19 y): 28 % not up-to-date.

    • Oregon 2012 (2 mo–6 y cases): 31 % unvaccinated, 24 % undervaccinated.

    • California 2014 (222 infants <12 mo): only 24 % had ≥1 DTaP dose; yet 51 % were age-eligible (>2 mo).

  • Several outbreaks occurred in highly vaccinated cohorts (e.g., Massachusetts schools, Wisconsin county, etc.) illustrating impact of waning immunity.

Reasons for Non-vaccination (9 reports, 12 outbreaks)

  • Personal belief/philosophical: up to 70 % (Oregon 2012).

  • Religious: 59–93 % (multiple Massachusetts outbreaks 1986-88); 84 % (Florida 2013).

  • Cultural (Amish): 72 % (Delaware 2004-05); 79 % (Illinois 2009-10).

  • Other: illness at scheduled doses, missed appointments, provider hesitation.

Risk Analyses

  • Individual-level:

    • Colorado 1987-98 cohort: exemptions → 5.9\times higher pertussis risk.

    • Managed-care case–control 1996-2007: exemptions → nearly 20\times risk; 11 % of cases attributable to refusal.

    • Vaccine Safety Datalink 2004-10: undervaccination risk rises with each missed DTaP dose.

  • Community-level:

    • Higher school/community exemption rates in CO, MI, NY, CA linked to higher pertussis incidence in both exempt & vaccinated.

    • States permitting personal-belief exemptions or with easier procedures show ≈1.5\times higher pertussis incidence.

    • Spatial clustering of refusers cannot be explained by waning immunity alone.

Timelines & Milestones (Box 1 Recap)

Measles

  • 1963 vaccine licensed → 1988 incidence 1.3/1 000 000.

  • 1989–92 resurgence due to low preschool coverage.

  • 1989 second-dose policy; elimination declared 2000.

  • 2014 Disneyland outbreak marks largest post-elimination spike.

Pertussis

  • 1940s whole-cell vaccine adoption; nadir 1976.

  • 1990s acellular replacement; 2005 Tdap booster.

  • 2010 CA epidemic (9 154 cases); 2014 CA epidemic (9 935 cases).

Key Numerical & Statistical Highlights

  • Measles post-2000: n=1\,416 cases; 56.8\% unvaccinated; 70.6\% of eligible unvaccinated held NMEs.

  • Measles individual risk: RR_{exempt/vaccinated}=35 (nationwide); 22 (Colorado).

  • Pertussis individual risk:

    • RR_{exempt/vaccinated}=5.9 (Colorado);

    • OR_{exempt/vaccinated}\approx20 (managed care).

  • Waning DTaP immunity: OR_{pertussis}=1.33 per year since last dose.

Ethical, Philosophical & Practical Implications

  • Ethical tension: parental autonomy vs child welfare & community protection.

  • Public-health justification for mandates strengthened where refusal imposes sizable, quantifiable harm (e.g., 35\times measles risk).

  • Policies considered:

    • Tighten exemption criteria (e.g., CA SB-277 eliminated personal-belief exemptions post-2015).

    • School enforcement, conditional admission, outbreak-specific exclusions.

    • Provider education to address safety misconceptions, trust deficits.

  • Recognize heterogeneous drivers of hesitancy: perceived disease severity, vaccine safety beliefs, religious/cultural doctrines, institutional trust.

Limitations of the Evidence Base

  • No formal study-quality grading performed.

  • Potential biases (ascertainment, misclassification) likely under-estimate true risk associated with exemptions.

  • Pertussis analysis confounded by waning immunity & diagnostic variability; chains of transmission rarely fully mapped.

Conclusions (Author Summary)

  • Post-elimination measles outbreaks: large share of cases intentionally unvaccinated; refusal increases risk for both refusers & vaccinated peers.

  • Pertussis resurgence multifactorial (waning immunity, acellular vaccine performance), yet refusal/undervaccination still elevates risk in some populations.

  • Evidence supports strengthening immunization mandates while simultaneously engaging vaccine-hesitant populations through education & trust-building.

Selected References for Further Study

  • Salmon DA et al., JAMA 1999 – risk among religious/philosophical exemptions.

  • Omer SB et al., JAMA 2006 – state exemption policies & pertussis incidence.

  • Klein NP et al., NEJM 2012 – waning protection after 5th DTaP.

  • McGirr A & Fisman DN, Pediatrics 2015 – meta-analysis of DTaP immunity duration.

(All data & quotations copyright 2016 American Medical Association; reproduced for educational study-note purposes.)

Overview & Purpose

  • This review article, published in JAMA in 2016, specifically examined the quantitative link between vaccine delay, refusal, or exemption and the epidemiology of two significant vaccine-preventable diseases: measles and pertussis, which have experienced recent outbreaks in the U.S.

  • The study highlights the importance of understanding this link due to the resurgence of these diseases and recurring outbreaks, despite high overall national vaccine coverage rates. It emphasizes the need for a precise, quantitative understanding of the risks directly attributable to intentional non-vaccination.

  • The primary objective was to systematically summarize published U.S. literature that connects vaccine refusal (including delay, exemption, and other forms of intentional non-vaccination) to disease occurrence.

    • For measles, the focus was on studies conducted after its declared elimination (post-January 1, 2000).

    • For pertussis, the focus was on studies conducted after its incidence nadir (post-January 1, 1977).

Background: Coverage, Exemptions & Hesitancy

  • As of 2013, national vaccine coverage rates for children aged 19–35 months were notably high:

    • 91.9\% for those who received at least one dose of the MMR (Measles, Mumps, Rubella) vaccine.

    • 83.1\% for those who received at least four doses of the DTaP (Diphtheria, Tetanus, and acellular Pertussis) vaccine.

  • Despite these high overall coverage rates, nonmedical exemptions (NMEs) from school immunization requirements have been steadily rising for over two decades.

    • NMEs typically include waivers based on religious beliefs or personal/philosophical objections.

    • Initially, the rise in NMEs was predominantly observed in states with historically easy personal-belief exemption policies. More recently, this trend has expanded to include states where obtaining such exemptions is moderately difficult, as well as those that restrict exemptions primarily to religious reasons.

  • Public and political attention is often galvanized by significant outbreaks, such as the widely publicized 2014 Disneyland measles outbreak. This single event resulted in 111 cases spread across 7 U.S. states, along with cases in Canada and Mexico. Approximately 50\% of these cases were among unvaccinated individuals, with the majority having chosen not to vaccinate.

Methods (Literature Search Strategy)

Measles

  • A comprehensive PubMed search was conducted up to November 30, 2015.

  • The search utilized various combinations of keywords: “measles”, “vaccinated/unvaccinated”, “outbreak”, “import*” (to capture terms like “importation”), and “MMWR” (Morbidity and Mortality Weekly Report).

  • The search was specifically limited to studies conducted in the U.S. and published from January 1, 2000, onwards, aligning with the post-elimination period.

  • A separate, unrestricted search was performed for the phrase “measles risk exemption” to capture additional relevant studies.

Pertussis

  • A PubMed search was conducted up to November 30, 2015, focusing on non-overlapping state and community outbreaks that occurred after January 1, 1977, corresponding to the post-nadir period.

  • The primary keywords used were: “pertussis epidemic/endemic/outbreak/MMWR”.

  • Additional keywords were incorporated without any date limits to broaden the search for relevant studies: “pertussis vaccine refusal/exemption/delay/hesitan/undervaccination/cluster” (where “hesitan” would capture terms like “hesitancy”).

Results – Measles

Recent U.S. Epidemiology

  • Following the licensure of the measles vaccine in 1963, there was a dramatic decline in the incidence of measles in the U.S. The disease was officially declared eliminated in 2000.

  • However, 2014 witnessed a significant spike, with 23 separate outbreaks contributing to a total of 668 U.S. cases. This represented the largest annual total of measles cases reported post-elimination.

Outbreak Compilation (2000-2015)

  • A compilation of 18 key reports from this period revealed a total of 1,416 measles cases, with patient ages ranging from 2 weeks to 84 years; 178 of these cases occurred in infants younger than 12 months.

    • A substantial majority, 56.8\% (804 cases), had never received the measles vaccine.

    • Only 199 cases (14.1\%) were among individuals who had been previously vaccinated.

    • Among the 574 age-eligible unvaccinated cases (i.e., those old enough to have received the vaccine), 405 (70.6\%) cases, accounting for 41.8\% of all cases, held nonmedical exemptions (NMEs).

  • Analysis of the cumulative epidemic curve across these 18 outbreaks (totaling 145 cases with detailed generation data) showed:

    • 111 cases were unvaccinated, 11 had unknown vaccination status, and 23 were vaccinated.

    • Unvaccinated individuals predominantly accounted for the index cases (first cases in an outbreak) and early first-generation spread, indicating their role in initiating and propagating outbreaks.

    • These outbreaks typically extended for up to 5 generations, with the latest recorded case appearing approximately 12 weeks after the initial case.

Individual & Community Risk Studies

  • A national study examining measles cases from 1985 to 1992 found significant risk disparities:

    • Children with vaccine exemptions faced a 35\times higher risk of contracting measles compared to fully vaccinated children.

    • The onset of measles resurgence was observed approximately 1 year earlier in populations with higher rates of exempted individuals.

    • Modeling studies further demonstrated that a higher degree of local clustering of vaccine exemptions led to a higher incidence of measles, even within the vaccinated population, due to reduced herd immunity.

  • Data from Colorado between 1987 and 1998 reinforced these findings:

    • Individuals with vaccine exemptions had a 22\times higher risk of measles compared to vaccinated individuals. The greatest absolute risk was observed in children aged 3–10 years.

    • County-level exemption rates positively correlated with county measles incidence, suggesting a community-wide impact.

    • Among index and first-generation cases, 14.5\% were exempted, compared to 7.1\% in later generations, again highlighting the role of unvaccinated individuals in early transmission.

Results – Pertussis

Recent U.S. Epidemiology & Contributing Factors

  • The widespread adoption of the whole-cell pertussis vaccine in the 1940s led to a dramatic reduction in incidence, reaching a nadir of 1,010 cases in 1976.

  • The acellular pertussis vaccine (DTaP) began replacing the whole-cell vaccine in the 1990s, and the Tdap booster (for adolescents and adults) was licensed in 2005.

  • Despite these advancements, annual U.S. pertussis cases have risen significantly, now consistently exceeding 10,000, with more than 25,000 cases reported in each of the three years preceding the review.

  • Waning immunity is considered a pivotal factor in the resurgence:

    • Observational data consistently show that a longer interval since the last DTaP/Tdap dose is associated with a higher risk of pertussis.

    • A meta-analysis quantified this effect, showing that the odds of pertussis increase 1.33-fold for each year that passes since the last DTaP dose.

Outbreak Compilation (1977-2015)

  • A total of 32 non-overlapping outbreak reports were analyzed, encompassing 10,609 cases with documented vaccine status, ranging in age from 10 days to 87 years.

  • Five of the largest statewide epidemics consistently showed substantial inadequate vaccination status among cases:

    • Arizona 1988: Of 598 age-eligible cases, 33\% had received fewer than 3 DTaP doses.

    • California 2010: Among 4,415 cases aged 6 months to 18 years, 45\% were under- or unvaccinated (including 380 completely unvaccinated individuals and 1,621 undervaccinated).

    • Washington 2012: In 1,829 cases aged 3 months to 19 years, 28\% were not up-to-date with their vaccinations.

    • Oregon 2012: Among cases aged 2 months to 6 years, 31\% were entirely unvaccinated, and 24\% were undervaccinated.

    • California 2014: Among 222 infants younger than 12 months, only 24\% had received at least one DTaP dose, despite 51\% being age-eligible (i.e., older than 2 months).

  • Several outbreaks also occurred in cohorts with high overall vaccination rates (e.g., in Massachusetts schools and a Wisconsin county), further illustrating the significant impact of waning immunity even in vaccinated populations.

Reasons for Non-vaccination (9 reports, 12 outbreaks)

  • The primary stated reasons for non-vaccination in the analyzed outbreaks included:

    • Personal belief/philosophical reasons: Cited by up to 70\% of non-vaccinated individuals in the Oregon 2012 outbreak.

    • Religious reasons: Ranged from 59-93\% in multiple Massachusetts outbreaks (1986-88) and 84\% in a Florida 2013 outbreak.

    • Cultural reasons (e.g., Amish communities): Accounted for 72\% in the Delaware 2004-05 outbreak and 79\% in the Illinois 2009-10 outbreak.

    • Other reasons: Included temporary illness at the time of scheduled doses, missed appointments, and provider hesitation or misinformation.

Risk Analyses

  • Individual-level studies consistently demonstrated elevated pertussis risk among the unvaccinated:

    • In a Colorado cohort from 1987-98, individuals with exemptions faced a 5.9\times higher risk of pertussis.

    • A managed-care case–control study from 1996-2007 found that exemptions were associated with a nearly 20\times higher risk of pertussis. This study estimated that 11\% of all pertussis cases were attributable to vaccine refusal.

    • Data from the Vaccine Safety Datalink (2004-10) showed that the risk of pertussis in undervaccinated individuals increased proportionally with each missed DTaP dose.

  • Community-level studies indicated broader impacts of non-vaccination clusters:

    • Higher school or community exemption rates in states like Colorado, Michigan, New York, and California were consistently linked to higher pertussis incidence, affecting both exempted and vaccinated individuals in those communities.

    • States that permit personal-belief exemptions or have easier exemption procedures generally showed an approximate 1.5\times higher pertussis incidence compared to states with stricter policies.

    • Spatial clustering of vaccine refusers was identified as a significant factor in pertussis outbreaks, a phenomenon that could not be fully explained by waning immunity alone.

Timelines & Milestones (Box 1 Recap)

Measles

  • 1963: Measles vaccine is licensed, leading to a dramatic decline in disease incidence.

  • 1988: Incidence rate falls to 1.3 per 1,000,000 population.

  • 1989–92: A resurgence of measles occurs, primarily attributed to low vaccination coverage rates among preschool-aged children.

  • 1989: The policy for a second dose of measles vaccine is introduced to improve immunity.

  • 2000: Measles is officially declared eliminated in the United States.

  • 2014: The Disneyland outbreak marks the largest spike in measles cases post-elimination, highlighting ongoing vulnerabilities.

Pertussis

  • 1940s: The whole-cell pertussis vaccine is widely adopted, leading to a significant reduction in disease burden.

  • 1976: Incidence reaches a nadir with 1,010 recorded cases.

  • 1990s: Acellular pertussis vaccine replaces the whole-cell vaccine in the routine immunization schedule.

  • 2005: The Tdap booster vaccine (for adolescents and adults) is licensed, aiming to extend protection.

  • 2010: California experiences a major epidemic with 9,154 recorded cases.

  • 2014: Another significant California epidemic occurs, with 9,935 cases, underscoring ongoing challenges in pertussis control.

Key Numerical & Statistical Highlights

  • Measles (post-2000 outbreaks):

    • A total of n=1\,416 cases were reviewed. Of these, 56.8\% were unvaccinated.

    • Among age-eligible unvaccinated cases, 70.6\% held nonmedical exemptions (NMEs).

  • Measles individual risk (relative risk of measles for exempted vs. vaccinated individuals):

    • Nationwide studies: Relative Risk (RR_{exempt/vaccinated}) = 35\

    • Colorado studies: Relative Risk (RR_{exempt/vaccinated}) = 22\

  • Pertussis individual risk (relative risk or odds ratio for exempted vs. vaccinated individuals):

    • Colorado cohort: Relative Risk (RR_{exempt/vaccinated}) = 5.9\

    • Managed-care case–control study: Odds Ratio (OR_{exempt/vaccinated}) \approx20\ (indicating nearly 20 times the risk).

  • Waning DTaP immunity: The odds of pertussis increase by 1.33-fold for each year that passes since the last DTaP dose.

Ethical, Philosophical & Practical Implications

  • Ethical Tension: The reviewed evidence brings into sharp focus the inherent tension between parental autonomy regarding healthcare decisions and the broader public health responsibilities concerning child welfare and community protection.

  • Public-Health Justification for Mandates: The findings strengthen the public-health justification for immunization mandates, particularly in scenarios where vaccine refusal imposes a sizable and quantifiable harm on both the individual and the community (e.g., the reported 35\times higher risk of measles in exempted individuals).

  • Policy Considerations: The article suggests several policy avenues:

    • Tightening exemption criteria: exemplified by California's SB-277, which eliminated personal-belief exemptions post-2015.

    • Enhanced school enforcement: including conditional admission policies and outbreak-specific exclusions for unvaccinated students.

    • Provider education: initiatives aimed at addressing common safety misconceptions about vaccines and rebuilding trust deficits between healthcare providers and hesitant parents.

  • Understanding Hesitancy: It's crucial to recognize the heterogeneous drivers behind vaccine hesitancy, which can include varying perceptions of disease severity, specific beliefs about vaccine safety, deeply held religious or cultural doctrines, and levels of trust in medical institutions or public health authorities.

Limitations of the Evidence Base

  • No Formal Study-Quality Grading: The review did not include a formal grading of the quality of individual studies, which could impact the overall strength of the evidence.

  • Potential Biases: The findings may be subject to various biases, such as ascertainment bias (where cases among unvaccinated individuals might be more readily identified) and misclassification bias (e.g., vaccinated individuals misclassified as unvaccinated, or vice versa). These biases likely lead to an underestimation of the true risk associated with vaccine exemptions.

  • Pertussis Analysis Complexities: The analysis of pertussis outbreaks is particularly confounded by:

    • Waning immunity: The decreasing protection over time from current vaccines makes it challenging to isolate the impact of vaccine refusal.

    • Diagnostic variability: Differences in diagnostic methods and reporting across different outbreaks and regions can complicate data interpretation.

    • Unmapped Transmission Chains: Chains of pertussis transmission are rarely fully mapped, making it difficult to precisely attribute spread solely to unvaccinated individuals versus other factors.

Conclusions (Author Summary)

  • Measles Outbreaks: Post-elimination measles outbreaks in the U.S. demonstrate that a large share of cases occur in intentionally unvaccinated individuals. Vaccine refusal significantly increases the risk not only for the refusers themselves but also for vaccinated individuals within their communities due to reduced herd immunity.

  • Pertussis Resurgence: The resurgence of pertussis is recognized as multifactorial, influenced by factors such as waning immunity from the acellular vaccine and its performance characteristics. Nevertheless, vaccine refusal and undervaccination still substantially elevate the risk of pertussis in certain populations and contribute to outbreaks.

  • Policy Recommendations: The cumulative evidence supports the strengthening of immunization mandates. Concurrently, it emphasizes the importance of continuing to engage vaccine-hesitant populations through targeted, evidence-based education and trust-building initiatives to address underlying concerns.

Selected References for Further Study

  • Salmon DA et al., JAMA 1999 – A foundational study on the risk of vaccine-preventable diseases among children with religious or philosophical exemptions.

  • Omer SB et al., JAMA 2006 – Research exploring the association between state exemption policies and the incidence of pertussis.

  • Klein NP et al., NEJM 2012 – A key study examining the waning protection against pertussis after the fifth dose of DTaP vaccine.

  • McGirr A & Fisman DN, Pediatrics 2015 – A meta-analysis providing further insights into the duration of DTaP immunity.

(All data & quotations copyright 2016 American Medical Association; reproduced for educational study-note purposes.)