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  • Primary Vaccination during InfancyCorrelates with Humoral Immune Response following

    Induced Cell-Mediated ImmunityHepatitis B Virus Vaccine

    Laura Gelinas, Bahaa Abu-Raya, Candice Ruck, Bing Cai and Tobias R. Kollmann


    2017, 1 (4) 42-52ImmunoHorizons

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  • Hepatitis B Virus VaccineInduced Cell-Mediated ImmunityCorrelates with Humoral Immune Response following PrimaryVaccination during Infancy

    Laura Gelinas,*,1 Bahaa Abu-Raya,,,1 Candice Ruck,* Bing Cai, and Tobias R. Kollmann,

    *Department of Experimental Medicine, University of British Columbia, Vancouver, British Columbia V5Z 1M9, Canada; Vaccine Evaluation Center,

    University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada; and Department of Pediatrics, University of British Columbia,

    Vancouver, British Columbia V6H 3V4, Canada


    Data on hepatitis B virus (HBV) vaccineinduced cell-mediated immunity (CMI) and humoral immune response during infancy is

    scarce. We assessed HBV vaccineinduced CMI among infants stratified as nonresponders (Ab against HBV surface Ag [anti-HBs]

    levels ,10 IU/l), low-responders (anti-HBs levels 10100 IU/l), and high-responders (anti-HBs levels $100 IU/l) following their

    primary vaccination against HBV. Moreover, we assessed the association between HBV vaccineinduced CMI and anti-HBs levels.

    Infants were immunized with HBV vaccine at ages 2, 4, and 6 mo. Hepatitis B surface Ag (HBsAg)-specific proliferation, intracellular

    cytokine production, and bulk cytokine secretion were assessed on PBMCs collected at 1 y and anti-HBs levels were measured at 1

    and 2 y of age. Infants classified at 2 y of age as low-responders (n = 28) had lower median levels of secreted IFN-g than high-

    responders (n = 29), 17.15 pg/ml versus 33.16 pg/ml, respectively, p = 0.009. Infants classified at 2 y of age as nonresponders (n = 15)

    had lower median levels of secreted TNF-a than high-responders (n = 29), 116.11 pg/ml versus 162.27 pg/ml, respectively, p = 0.032.

    There was a positive correlation between HBsAg-specific secreted IFN-g levels at 1 y and anti-HBs levels at 1 and 2 y of age, rho =

    0.269 and 0.302, respectively, (p = 0.019 and p = 0.01, respectively). There was a positive correlation between anti-HBs levels at age 1

    y and the levels of secreted IL-10, rho = 0.297, p = 0.009. HBsAg-specific IFN-g, IL-10, and TNF-a secretion correlated with HBV

    vaccineinduced humoral immune response. Assessment of CMI is a useful adjunct in demonstrating the persistence of HBV

    vaccineinduced memory immune response. ImmunoHorizons, 2017, 1: 4252.


    Infection with hepatitis B virus (HBV) is a global public healthconcern, with a worldwide estimate of more than two billionindividuals infected at somepoint in their lives (1). In some regionsof the world, including sub-Saharan Africa, HBV is hyperendemic

    ($8% hepatitis B surface Ag [HBsAg] prevalence) (2). The burdenofHBV infection is chieflydrivenby infections acquired in thefirstyears of life (3). In southern and eastern sub-Saharan Africa, anincrease in chronic hepatitis B infection occurred among youngchildren from 1990 to 2005, reaching a prevalence of 89% inchildren 09 y old (3). InNorth America, although the prevalence

    Received for publication May 2, 2017. Accepted for publication May 25, 2017.

    Address correspondence and reprint requests to: Dr. Bahaa Abu-Raya, Division of Infectious Diseases, Department of Pediatrics, University of British Columbia, BCChildrens Hospital, Ambulatory Care Building, K4-165 - 4480 Oak Street, Vancouver, BC V6H 3V4, Canada. E-mail address: bahaa.aburaya@cw.bc.ca

    ORCID: 0000-0003-3713-4275 (L.G.).1L.G. and B.A. are joint first authors.

    This work was supported in part by National Institute of Allergy and Infectious Diseases, National Institutes of Health Grant N01 AI50023. T.R.K. is supported in part by aCareer Award from the Michael Smith Foundation for Health Research.

    Abbreviations used in this article: anti-HBs, Ab against HBV surface Ag; CMI, cell-mediated immunity; HBsAg, hepatitis B surface Ag; HBV, hepatitis B virus; IQR,interquartile range; rcf, relative centrifugal force; RT, room temperature.

    The online version of this article contains supplemental material.

    This article is distributed under the terms of the CC BY 4.0 Unported license.

    Copyright 2017 The Authors

    42 https://doi.org/.4049/immunohorizons.1700015


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  • ofHBV infection has declined in the postvaccination era, children04 y of age still haveHBsAg positivity rates of nearly 2% in 2005,representing the highest age-specific positivity rate (3). Infectionsacquired during thefirst 5 y of life carry a high risk (nearly 30%) ofprogression to chronic disease (3, 4). Among immigrants to NorthAmerica, the prevalence of chronicHBV infection is ~5% and 40%of them develop advanced liver disease (5). In Canada, nearly300,000 individuals who were born abroad have chronic HBVinfection. The socioeconomic burden of this condition among thispopulation is significant (5).

    Although a decline in the prevalence of HBV infectionfollowing expanded HBV vaccination has been established(3), breakthrough infections have been reported after primaryvaccination against HBV (69).

    Measurement of the humoral immune response (Ab againstHBV surface Ag [anti-HBs] Ab levels) is currently the mostcommonly employed immune marker that correlates with pro-tection fromHBV infection. It is generally accepted that anti-HBslevels$10 IU/l are considered protective against HBV infection(1012). In the vaccinated population, up to 10% of individualsonly achieve anti-HBs levels of,10 IU/l despite full vaccination(termed nonresponders) (1). However, some data suggest thatmany individuals whose levels are ,10 IU/l are still protectedagainst HBV infection (13, 14). On the other hand, there is noabsolute protection against HBV infection at any anti-HBs levels(11).CasesofHBV infectionoccur inhealthy individualswithanti-HBs levels between 10 and 100 IU/l (termed low-responders)(11, 15, 16) and those with anti-HBs levels $100 IU/l (termedhigh-responders) (11).

    The finding that protection from HBV infection in subjectswith anti-HBs levels ,10 IU/l (13, 14) and the potential forinfectionwithHBV inpersonswhose anti-HBs levels are.10 IU/l(11, 15, 16) indicates that the full mechanisms of vaccine-inducedprotection are yet to be determined.

    Cell-mediated immunity (CMI) may correlate with humoralimmune response to HBV vaccination. To date, studies that haveattempted to elucidate the biological mechanisms driving thehumoral response to theHBVvaccinehavebeenconductedmainlyin adult populations and have thus far yielded inconsistent results.Sufficient data on these questions in infant cohorts is currentlylacking.

    Adult studies, inherently limited by the necessity of including aheterogeneous population of postprimary and postbooster vacci-nated subjects, reported a correlation betweenanti-HBs levels andT cell proliferation (1719). Other studies reported a lack of T cellproliferative responses to HBsAg among nonresponders to HBVvaccine booster dose (1921). Although one study reported thatinfant nonresponders to primary vaccination secreted less IFN-gthan responders (22), the correlation between anti-HBs levels andIFN-g production remained inconclusive, as this finding wasconfirmed in some (23) but refuted in other studies (14, 24, 25). Inone study in infants, nonresponders to primary vaccinationagainst HBV secreted less IL-10 than responders (22).Similarresults have been observed in adult populations (23, 26, 27). Last,TNF-a was found to be produced at significantly lower levels in

    adult nonresponders as compared with responders following invitro stimulation with H


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