Accepted Manuscript

Vaccination-Induced Herd Immunity: Successes and Challenges

Michael L. Mallory, B.S, Lisa C. Lindesmith, M.S, Ralph S. Baric, PhD

PII: S0091-6749(18)30762-0
DOI: 10.1016/j.jaci.2018.05.007
Reference: YMAI 13438

To appear in: Journal of Allergy and Clinical Immunology

Received Date: 10 January 2018

Revised Date: 26 April 2018
Accepted Date: 4 May 2018

Please cite this article as: Mallory ML, Lindesmith LC, Baric RS, Vaccination-Induced Herd Immunity:
Successes and Challenges, Journal of Allergy and Clinical Immunology (2018), doi: 10.1016/
j.jaci.2018.05.007.

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1 Vaccination-Induced Herd Immunity: Successes and Challenges

2 Michael L. Mallory (B.S), Lisa C. Lindesmith (M.S), Ralph S. Baric (PhD)

3 Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA

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4 Corresponding author: Ralph S. Baric, PhD

5 3304 Hooker Research Center

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7 135 Dauer DR

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10 Gillings School of Global Public Health
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12 University of North Carolina-Chapel Hill
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14 Chapel Hill, NC 27599
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919-966-3895 (office)
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18 919-966-0584 (fax)
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20 rbaric@email.unc.edu

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22 Word Count: 1161

23 Key words: herd immunity, vaccination, neutralizing antibodies

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24 Abbreviations: HPV, human papillomavirus; RNA, ribonucleic acid, GII.4, norovirus

25 genogroup II, genotype 4; DENV 1-4, dengue virus serotypes 1-4

26 Conflict of Interest Statement: MLM, LCL and RSB do not have a commercial or other

27 association that might pose a conflict of interest.

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28 The World Health Organization estimates that global vaccination programs save 2-3

29 million lives per year by priming the immune system to protect against pathogenic threats that

30 pose significant global health and economic burdens (Figure 1A)(1). Besides individual

31 protection, vaccination programs also rely on population or “herd” immunity: the immunization

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32 of large portions of the population to protect the unvaccinated, immunocompromised, and

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33 immunologically naïve by reducing the number of susceptible hosts to a level below the

34 threshold needed for transmission. For example, immunization of >80% of the global population

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35 against smallpox virus reduced transmission rates to uninfected individuals to a point low

36 enough to achieve eradication of the virus(1). Similarly, although the extent of coverage needed

37
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is pathogen specific, poliovirus is now targeted for eradication, with only Pakistan, Afghanistan,
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38 and Nigeria documenting endemic viral infections(1).
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39 Despite the success of select vaccination programs, societal and biological factors (Figure

40 1B), including the inability of population groups to generate protective immunity in response to
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41 vaccination is a challenge for achieving herd immunity. The unvaccinated, including the very
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42 young, aged, and those who are immunocompromised due to infection, congenital conditions or

43 medical history, must be protected by passive immunity. For example, unvaccinated females
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44 benefit from human papillomavirus (HPV) vaccination of their male partners, as HPV strains 16
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45 and 18 are linked to 70-80% of cases of cervical cancer(2). While both males and females can be
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46 infected with HPV, females are more likely to experience detrimental oncogenic effects,

47 including loss of reproductive capabilities. The vaccination of females and males in young

48 populations with attenuated vaccines of the circulating HPV strains has decreased transmission

49 of these specific HPV viruses to young unvaccinated females in Scotland and Australia(2). Thus,

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50 vaccination of the potential carriers within the population can promote disease prevention in the

51 unvaccinated.

52 Immune senescence, immaturity, and imprinting limit human vaccine responses. These

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53 issues pose challenging obstacles to the development of vaccine-induced broadly protective

54 long-lasting immunity. Immunosenescence refers to the progressive loss of responsiveness to a

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55 pathogen, resulting in decreased antibody titer or cellular responses, requiring booster

vaccinations to restore immunity. In the late 20th century, measles was nearly eradicated in

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57 China, Korea and the United States as the result of early-age vaccination and boosters with

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58 attenuated virus(3, 4). However, re-introduction of the wild-type virus into these localities has
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59 caused spikes of infection in immunized middle-aged adults and has been linked to the wild-type

60 measles virus’ capacity to overcome reduced antibody titers in these more aged populations(3,
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61 4), indicating a prospective need for a tertiary booster in adults to bolster neutralization titers.
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62 The breadth and length of duration of herd immunity are also dependent upon
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63 characteristics of the pathogen and its interactions with the immune system. Antigenic drift,

64 antigenic shift, and recombination result in antigenic diversity within a pathogen pool, and a viral
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65 species can consist of multiple variants that are antigenically distinct from each other. The lack

66 of a proof-reading function associated with most RNA polymerases makes RNA viruses
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67 particularly adept at generating strain diversity. For example, norovirus, the leading cause of
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68 acute gastroenteritis, has >30 genotypes. The GII.4 genotype evolves rapidly at surface epitopes

69 that are key targets of protective immunity/neutralizing antibodies (8). Despite maintaining

70 93.9% amino acid sequence homology between the earliest and most recent known pandemic

71 strains, evolution at hypervariable epitopes correlates with pandemic bursts of disease

72 approximately every 2-5 years. The immunocompromised, immunosenescent, and young

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73 children have been postulated to be norovirus reservoirs. In these populations, a suppressed or

74 naïve immune system may not fully neutralize every viral variant. Lower immune pressure on

75 the virus, along with an error-prone RNA polymerase, allows for mutated variants to emerge and

76 escape neutralization.

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77 Pathogen-immune response interactions also shape Dengue and influenza virus immunity

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78 and subsequent vaccine design. Dengue circulates as four serotypes, (DENV1-4), which have

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79 roughly 70% sequence homology. Infection with one serotype induces production of both cross-

80 reactive and serotype-specific neutralizing antibodies during initial infection(5, 6). Upon

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81 infection with a second serotype, the original memory immune response is preferentially
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82 stimulated. Due to antigenic differences between the primary and secondary viruses, pre-existing

83 antibody is unable to effectively neutralize the second virus, allowing immune evasion through
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84 immune imprinting (original antigenic sin/antigenic seniority)(5, 6). Importantly, depending on

85 the level and neutralization capacity of the cross-reactive pre-existing antibodies, a secondary
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86 infection can cause severe disease(6). Similarly, the immune system preferentially recalls
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87 memory antibody responses to the earliest infecting strains of influenza A and norovirus and

88 shows weaker consecutive responses to infection with subsequent serotypes, respectively (8). As
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89 the herd is composed of individuals from many different age groups, and pandemic Influenza
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90 and norovirus strains change over time, effective vaccine development that induces broad
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91 protection is highly complicated by age and pre-exposure history. Conserved epitopes are

92 potential vaccine targets for these and other pathogens that are susceptible to antigenic drift/shift

93 and recombination. While progress toward a universal influenza vaccine is being made,

94 protection currently relies on regular vaccination with multiple attenuated circulating strains to

95 reduce transmission and mitigate disease severity(7). Despite a global surveillance network,

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96 predicting future flu epidemic strains for vaccine production is high risk, as evidence by

97 influenza vaccine-contemporary strain mismatches in both 2014-2015 and 2017-2018(8).

98 Norovirus, dengue, and influenza illustrate challenges in eliciting broad immunity

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99 through vaccination with a single serotype of attenuated virus. While vaccination would protect

100 against the vaccinated serotype, it has the potential to increase the severity of a secondary

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101 infection by inducing a dampened response to later variants based on antigenic variation,

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102 imprinting, and timing between inoculation and secondary infection and/or immune

103 enhancement(7, 9). Research focusing on protective immunity correlates, particularly cross-

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104 reactive neutralizing antibody titers, and chimeric serotype attenuated-viruses to elicit broad
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105 immunity is underway. Understanding and optimizing these factors may induce broad immunity

106 across populations.

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107 As vaccines that can overcome the challenges of poor immune responsiveness in hosts
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108 and antigenic diversity in pathogens are developed, public policy plays a critical role in
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109 achieving the high population vaccination rate needed to achieve herd immunity and freedom

110 from disease. Universal access to affordable health care is of the highest priority, as individuals
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111 of lower socioeconomic status often forgo vaccinations due to accessibility reasons, which can

112 leave large pockets of non-vaccinated, susceptible people who not only may suffer disease
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113 themselves but also facilitate transmission to others who are unable to get immunized, thus
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114 breaking the protective barrier herd immunity provides. The observed spike in incidents of

115 pertussis and measles in children and adults in the United States, indicates a need for effective

116 public education to counter anti-vaccination proponents whose fear of vaccine side-effects form

117 pockets of susceptibility and opportunity for spread of pathogens among those who are

118 immunocompromised or otherwise unable to receive a vaccine. The more accessible we make

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119 vaccination through education programs, minute clinics, job-site resources, and lowered costs,

120 the more effective vaccination programs will be. To reach the goal of protection from disease

121 and eradication of pathogens through vaccination, governments, scientists, and citizens will have

122 to commit resources equivalent to the diversity and abundance of the pathogens we fight.

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123

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124 Acknowledgements:

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125 This work was supported by grants from the National Institutes of Health, Allergy and Infectious

126 Diseases (R56 A15-0756 and U19 AI109761 CETR) and the Wellcome Trust (A17-0915-001).

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128 Figure Legend

129 Figure 1. Biological and societal factors affecting vaccine-induced population immunity

130 (Panel A) and the impact of vaccination on prevalence of annual cases of Haemophilus

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131 influenzae b (1986-1990), Measles (1950-1954), Pertussis (1938-1942), and Poliomyelitis

132 (1950-1954) in Canada pre and post-vaccine era (Panel B) (10). Solid bars represent annual

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133 cases pre-era, dates listed above, while hatched bars represent annual cases post-era (2007-

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134 2011). Panel B is a reproduction of the data made publicly available by Jones, DB at The

135 Chief Public Health Officer’s Report on the State of Public Health in Canada 2013-

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136 Immunization and Vaccine-Preventable Diseases-Staying Protected:
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137 https://www.canada.ca/content/dam/phac-aspc/migration/phac-aspc/cphorsphc-

138 respcacsp/2013/assets/pdf/2013-eng.pdf.
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154 References

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