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Human Vaccines & Immunotherapeutics Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/khvi20
Inactivated human rotavirus vaccine induces heterotypic antibody response: Correction and development of IgG avidity assay a
a
Daniel E. Velasquez , Yuhuan Wang & Baoming Jiang
a
a
Division of Viral Diseases, Centers for Disease Control and Prevention, Atlanta, USA Accepted author version posted online: 18 Feb 2015.
Click for updates To cite this article: Daniel E. Velasquez, Yuhuan Wang & Baoming Jiang (2015): Inactivated human rotavirus vaccine induces heterotypic antibody response: Correction and development of IgG avidity assay, Human Vaccines & Immunotherapeutics, DOI: 10.4161/21645515.2014.988553 To link to this article: http://dx.doi.org/10.4161/21645515.2014.988553
Disclaimer: This is a version of an unedited manuscript that has been accepted for publication. As a service to authors and researchers we are providing this version of the accepted manuscript (AM). Copyediting, typesetting, and review of the resulting proof will be undertaken on this manuscript before final publication of the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal relate to this version also.
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
Letter to the Editor Inactivated human rotavirus vaccine induces heterotypic antibody response: Correction and development of IgG avidity assay Daniel E. Velasquez, Yuhuan Wang, Baoming Jiang
ip t
Division of Viral Diseases, Centers for Disease Control and Prevention, Atlanta, USA Address of correspondence:
cr
us
for Immunization and Respiratory Diseases, MS G04, 1600 Clifton Road NE, Atlanta, GA 30329. E-mail: [email protected].
an
Abstract: To improve lower efficacy among infants in low income countries and the safety (e.g., rare but severe intussusception) of live oral rotavirus vaccines, we have developed CDC-9 strain
M
with G1P[8] specificity as a candidate inactivated rotavirus vaccine (IRV). This IRV of three
ed
doses elicits high titers of IgG, neutralizing activity to homotypic and heterotypic human strains and IgG avidity in guinea pigs, thus is a promising alternative to enhance global immunization
pt
against rotavirus in children
ce
Keywords: rotavirus, IRV, CDC-9, heterotypic protection, IgG-avidity
Ac
Downloaded by [McMaster University] at 11:01 27 February 2015
Dr. Baoming Jiang, Gastroenteritis and Respiratory Viruses Laboratory Branch, National Center
1
To improve the safety (e.g., rare but severe intussusception) and lower immunogenicity and efficacy of live oral rotavirus vaccines among infants in low income countries, we have developed CDC-9 strain with G1P[8] specificity as a candidate inactivated rotavirus vaccine (IRV).
1, 2
This strain possesses desired biophysical, biochemical and virological characteristics
ip t
for an IRV, as it grows to high titer (up to 108 ffu/ml) in Vero cells and maintains predominant
triple-layered particles (>95%) during upstream manufacture and downstream purification
cr
us
was highly immunogenic even at a fractional dose of an intramuscular dose in mice. 3 Inactivated CDC-9 strain when formulated with alum adjuvant and administered intramuscularly induced
an
robust antibody response and protection from an oral challenge with a virulent homotypic human strain in gnotobiotic piglets. 4
M
We further conducted studies to address the heterotypic immunity and reported that a monovalent IRV induced broad cross-reactive neutralizing activity (NA) against human G1P[8],
ed
G9P[8], and G8P[4] strains in gnotobiotic piglets and guinea pigs 5. Regrettably, we reported
pt
rotavirus-specific IgG and NA in sera of IRV-immunized guinea pigs on incorrect days of post vaccination. Here we present correct kinetic data on homotypic and heterotypic antibody
ce
response in immunized guinea pigs (new Table 1). One dose of IRV significantly increased titers of IgG and NA against the two human strains, homotypic Wa G1P[8] (mean = 320, p =
Ac
Downloaded by [McMaster University] at 11:01 27 February 2015
processes. Inactivated CDC-9 strain alone when administered to skin using a microneedle patch
0.005) and heterotypic MW333 G8P[4] (mean = 176, p = 0.005). Meanwhile, the NA against the bovine WC3-human WI79 reassortant (G1P[5]) was low (mean = 28) and undetectable against the parent WC3 bovine strain. A second dose boosted IgG and NA against the strains Wa (mean = 2048; p = 0.008) and MW333 (mean = 704; p = 0.010) as well as the G1P[5] reassortant (mean = 176; p = 0.007). However, it barely improved NA against the WC3 strain (mean = 44). A third
2
dose further boosted IgG and NA against the strains Wa (mean = 3,072) and MW333 (mean = 1,152), but did not enhance NA against the WC3 strain and the G1P[5] reassortant virus. Of note, NA titers to the G1P[5] reassortant were significantly higher than the WC3 virus at post doses 2 (p = 0.010) and 3 (p = 0.007). No NA to the bovine-human WC3-WI79 (G6P[8]) reassortant was
ip t
detected in any of pre and post sera.
We also employed this collection of guinea pig sera to examine the kinetics and
cr
us
by developing a rotavirus-specific IgG avidity assay (Figure). All animals had undetectable levels of IgG or IgG avidity index in pre-bled sera. Like IgG titers, IgG avidity index increased
an
to a median value of 13% after dose 1, 42% after dose 2 and 51% after dose 3. The increases in avidity index from dose 1 to dose 2 and from dose 2 to dose 3 were significant.
M
In summary, we have demonstrated that IgG and NA responses to IRV in guinea pigs
ed
were dose-dependent. While one dose of IRV was able to induce elevated IgG and NA against homotypic and heterotypic human strains, two doses were needed to prompt NA against the
pt
G1P[5] reassortant or the parent WC3 virus. A third injection further boosted the titers of IgG and NA to homotypic and heterotypic human strains but also augmented the avidity of IgG, thus
ce
a three-dose regimen of a monovalent IRV is recommended for further clinical development in humans.
Ac
Downloaded by [McMaster University] at 11:01 27 February 2015
accumulated strength of IgG interactions with the multiple antigenic epitopes in virus particles
Acknowledgments
We thank W.J. Bellini and S. Mercader for assistance in developing rotavirus-specific IgG avidity assay and Stan Cryz of PATH for sponsoring the immunogenicity testing of IRV in guinea pigs.
3
The finding and conclusions in this report are those of the authors and do not necessarily
cr us an M ed pt ce Ac
Downloaded by [McMaster University] at 11:01 27 February 2015
ip t
represent the official positions of Centers for Disease Control and Prevention
4
References 1.
Jiang B, Gentsch JR, Glass RI. Inactivated rotavirus vaccines: a priority for accelerated
vaccine development. Vaccine 2008; 26:6754-8. 2.
Esona MD, Foytich K, Wang Y, Shin G, Wei G, Gentsch JR, Glass RI, Jiang B.
ip t
Molecular characterization of human rotavirus vaccine strain CDC-9 during sequential passages in Vero cells. Human vaccines 2010; 6:247-253.
cr
Moon S, Wang Y, Edens C, Gentsch JR, Prausnitz MR, Jiang B. Dose sparing and
us
enhanced immunogenicity of inactivated rotavirus vaccine administered by skin vaccination using a microneedle patch. Vaccine 2013; 31:3396-402.
Wang Y, Azevedo M, Saif LJ, Gentsch JR, Glass RI, Jiang B. Inactivated rotavirus
an
4.
vaccine induces protective immunity in gnotobiotic piglets. Vaccine 2010; 28:5432-6. Jiang B, Wang Y, Glass RI. Does a monovalent inactivated human rotavirus vaccine
M
5.
ed
induce heterotypic immunity? Evidence from animal studies. Human vaccines & immunotherapeutics 2013; 9:1634-7.
Jiang B, Wang Y, Saluzzo JF, Bargeron K, Frachette MJ, Glass RI. Immunogenicity of a
pt
6.
thermally inactivated rotavirus vaccine in mice. Human vaccines 2008; 4:143-7. Mercader S, Garcia P, Bellini WJ. Measles virus IgG avidity assay for use in
ce
7.
classification of measles vaccine failure in measles elimination settings. Clinical and vaccine
Ac
Downloaded by [McMaster University] at 11:01 27 February 2015
3.
immunology 2012; 19:1810-7.
5
Table 1. Rotavirus specific IgG and neutralizing activity in IRV-vaccinated guinea pigs
IgG
Pre (day 0)
Post dose 1 (day 30)
Post dose 2 (day 60)
Post dose 3 (day 74)
Human Vaccines & Immunotherapeutics Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/khvi20
Inactivated human rotavirus vaccine induces heterotypic antibody response: Correction and development of IgG avidity assay a
a
Daniel E. Velasquez , Yuhuan Wang & Baoming Jiang
a
a
Division of Viral Diseases, Centers for Disease Control and Prevention, Atlanta, USA Accepted author version posted online: 18 Feb 2015.
Click for updates To cite this article: Daniel E. Velasquez, Yuhuan Wang & Baoming Jiang (2015): Inactivated human rotavirus vaccine induces heterotypic antibody response: Correction and development of IgG avidity assay, Human Vaccines & Immunotherapeutics, DOI: 10.4161/21645515.2014.988553 To link to this article: http://dx.doi.org/10.4161/21645515.2014.988553
Disclaimer: This is a version of an unedited manuscript that has been accepted for publication. As a service to authors and researchers we are providing this version of the accepted manuscript (AM). Copyediting, typesetting, and review of the resulting proof will be undertaken on this manuscript before final publication of the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal relate to this version also.
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
Letter to the Editor Inactivated human rotavirus vaccine induces heterotypic antibody response: Correction and development of IgG avidity assay Daniel E. Velasquez, Yuhuan Wang, Baoming Jiang
ip t
Division of Viral Diseases, Centers for Disease Control and Prevention, Atlanta, USA Address of correspondence:
cr
us
for Immunization and Respiratory Diseases, MS G04, 1600 Clifton Road NE, Atlanta, GA 30329. E-mail: [email protected].
an
Abstract: To improve lower efficacy among infants in low income countries and the safety (e.g., rare but severe intussusception) of live oral rotavirus vaccines, we have developed CDC-9 strain
M
with G1P[8] specificity as a candidate inactivated rotavirus vaccine (IRV). This IRV of three
ed
doses elicits high titers of IgG, neutralizing activity to homotypic and heterotypic human strains and IgG avidity in guinea pigs, thus is a promising alternative to enhance global immunization
pt
against rotavirus in children
ce
Keywords: rotavirus, IRV, CDC-9, heterotypic protection, IgG-avidity
Ac
Downloaded by [McMaster University] at 11:01 27 February 2015
Dr. Baoming Jiang, Gastroenteritis and Respiratory Viruses Laboratory Branch, National Center
1
To improve the safety (e.g., rare but severe intussusception) and lower immunogenicity and efficacy of live oral rotavirus vaccines among infants in low income countries, we have developed CDC-9 strain with G1P[8] specificity as a candidate inactivated rotavirus vaccine (IRV).
1, 2
This strain possesses desired biophysical, biochemical and virological characteristics
ip t
for an IRV, as it grows to high titer (up to 108 ffu/ml) in Vero cells and maintains predominant
triple-layered particles (>95%) during upstream manufacture and downstream purification
cr
us
was highly immunogenic even at a fractional dose of an intramuscular dose in mice. 3 Inactivated CDC-9 strain when formulated with alum adjuvant and administered intramuscularly induced
an
robust antibody response and protection from an oral challenge with a virulent homotypic human strain in gnotobiotic piglets. 4
M
We further conducted studies to address the heterotypic immunity and reported that a monovalent IRV induced broad cross-reactive neutralizing activity (NA) against human G1P[8],
ed
G9P[8], and G8P[4] strains in gnotobiotic piglets and guinea pigs 5. Regrettably, we reported
pt
rotavirus-specific IgG and NA in sera of IRV-immunized guinea pigs on incorrect days of post vaccination. Here we present correct kinetic data on homotypic and heterotypic antibody
ce
response in immunized guinea pigs (new Table 1). One dose of IRV significantly increased titers of IgG and NA against the two human strains, homotypic Wa G1P[8] (mean = 320, p =
Ac
Downloaded by [McMaster University] at 11:01 27 February 2015
processes. Inactivated CDC-9 strain alone when administered to skin using a microneedle patch
0.005) and heterotypic MW333 G8P[4] (mean = 176, p = 0.005). Meanwhile, the NA against the bovine WC3-human WI79 reassortant (G1P[5]) was low (mean = 28) and undetectable against the parent WC3 bovine strain. A second dose boosted IgG and NA against the strains Wa (mean = 2048; p = 0.008) and MW333 (mean = 704; p = 0.010) as well as the G1P[5] reassortant (mean = 176; p = 0.007). However, it barely improved NA against the WC3 strain (mean = 44). A third
2
dose further boosted IgG and NA against the strains Wa (mean = 3,072) and MW333 (mean = 1,152), but did not enhance NA against the WC3 strain and the G1P[5] reassortant virus. Of note, NA titers to the G1P[5] reassortant were significantly higher than the WC3 virus at post doses 2 (p = 0.010) and 3 (p = 0.007). No NA to the bovine-human WC3-WI79 (G6P[8]) reassortant was
ip t
detected in any of pre and post sera.
We also employed this collection of guinea pig sera to examine the kinetics and
cr
us
by developing a rotavirus-specific IgG avidity assay (Figure). All animals had undetectable levels of IgG or IgG avidity index in pre-bled sera. Like IgG titers, IgG avidity index increased
an
to a median value of 13% after dose 1, 42% after dose 2 and 51% after dose 3. The increases in avidity index from dose 1 to dose 2 and from dose 2 to dose 3 were significant.
M
In summary, we have demonstrated that IgG and NA responses to IRV in guinea pigs
ed
were dose-dependent. While one dose of IRV was able to induce elevated IgG and NA against homotypic and heterotypic human strains, two doses were needed to prompt NA against the
pt
G1P[5] reassortant or the parent WC3 virus. A third injection further boosted the titers of IgG and NA to homotypic and heterotypic human strains but also augmented the avidity of IgG, thus
ce
a three-dose regimen of a monovalent IRV is recommended for further clinical development in humans.
Ac
Downloaded by [McMaster University] at 11:01 27 February 2015
accumulated strength of IgG interactions with the multiple antigenic epitopes in virus particles
Acknowledgments
We thank W.J. Bellini and S. Mercader for assistance in developing rotavirus-specific IgG avidity assay and Stan Cryz of PATH for sponsoring the immunogenicity testing of IRV in guinea pigs.
3
The finding and conclusions in this report are those of the authors and do not necessarily
cr us an M ed pt ce Ac
Downloaded by [McMaster University] at 11:01 27 February 2015
ip t
represent the official positions of Centers for Disease Control and Prevention
4
References 1.
Jiang B, Gentsch JR, Glass RI. Inactivated rotavirus vaccines: a priority for accelerated
vaccine development. Vaccine 2008; 26:6754-8. 2.
Esona MD, Foytich K, Wang Y, Shin G, Wei G, Gentsch JR, Glass RI, Jiang B.
ip t
Molecular characterization of human rotavirus vaccine strain CDC-9 during sequential passages in Vero cells. Human vaccines 2010; 6:247-253.
cr
Moon S, Wang Y, Edens C, Gentsch JR, Prausnitz MR, Jiang B. Dose sparing and
us
enhanced immunogenicity of inactivated rotavirus vaccine administered by skin vaccination using a microneedle patch. Vaccine 2013; 31:3396-402.
Wang Y, Azevedo M, Saif LJ, Gentsch JR, Glass RI, Jiang B. Inactivated rotavirus
an
4.
vaccine induces protective immunity in gnotobiotic piglets. Vaccine 2010; 28:5432-6. Jiang B, Wang Y, Glass RI. Does a monovalent inactivated human rotavirus vaccine
M
5.
ed
induce heterotypic immunity? Evidence from animal studies. Human vaccines & immunotherapeutics 2013; 9:1634-7.
Jiang B, Wang Y, Saluzzo JF, Bargeron K, Frachette MJ, Glass RI. Immunogenicity of a
pt
6.
thermally inactivated rotavirus vaccine in mice. Human vaccines 2008; 4:143-7. Mercader S, Garcia P, Bellini WJ. Measles virus IgG avidity assay for use in
ce
7.
classification of measles vaccine failure in measles elimination settings. Clinical and vaccine
Ac
Downloaded by [McMaster University] at 11:01 27 February 2015
3.
immunology 2012; 19:1810-7.
5
Table 1. Rotavirus specific IgG and neutralizing activity in IRV-vaccinated guinea pigs
IgG
Pre (day 0)
Post dose 1 (day 30)
Post dose 2 (day 60)
Post dose 3 (day 74)
