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Skin immunization against rotavirus using microneedles. Dr. Baoming Jiang Centers for Disease Control & Prevention Atlanta, USA bxj4@cdc.gov San Antonio, TX 8 October 2014. Rotavirus. •. Most common cause of severe. diarrhea in children. •. All children infected by age 5. •. - PowerPoint PPT Presentation
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Skin immunization against rotavirus using microneedles
Dr. Baoming Jiang
Centers for Disease Control & Prevention
Atlanta, USA
bxj4@cdc.gov
San Antonio, TX
8 October 2014
Rotavirus
• Most common cause of severe diarrhea in children
• All children infected by age 5
• First infections symptomatic• Natural immunity • Various strains/serotypes in circulation• Improvements in sanitation
don ’t prevent infection
Rotavirus Mortality by Country~453,000 deaths, 2008
100 to 1000 deaths per 100,000 50 to 100 deaths per 100,00010 to 50 deaths per 100,000
< 10 deaths per 100,000
Rotavirus Structure
RNA Segment Protein
1
2
34
5
6
7
8
9
10
11
VP1
VP2
VP3VP4
NSP1
VP6
NSP2
NSP3
VP7
NSP4
NSP5
VP2
VP4 Neutralization
antigen
VP6Subgroupantigen
VP7Neutralization
antigen
Subcore
P[8]G47.5%
P[8]G152.2%
P[6]G9 P[8]G92.3%
other18.2%
P[8]G32.8%
P[4]G211.5%
Summary of P & G Types of Rotavirus Childhood Diarrhea From 66 Published Studies
(1993-2003)
N=21,256Rare or regionally common strains (23 strainstotal): P[4]G1 (1.3%), P[6]G2 (0.8%), P[6]G1 (0.6%), P[6]G8 (0.6%), P[4], G3 (0.5%)
5.5%
Gentsch JID 2005
Two Live Oral Rotavirus VaccinesRotaTeq is Pentavalent & Rotarix is Monovalent
6
G1 G3
G2 G4
P[8]
Five bovine-humanreassortant rotavirus
strains
G1P[8]
Single human rotavirus strain
RotarixRotaTeq
Rotavirus Vaccines in US
Feb 2006 – RotaTeq licensed by FDA
Feb 2006 – RotaTeq recommended by ACIP
April 2008 – Rotarix licensed by FDA
June 2008 – Rotarix recommended by ACIP
Vaccine Introduced 2006
9
GAVI Co-Sponsored Trials in Africa and Asia
Kenya
South Africa
Malawi
Ghana
Mali
Rotarix
RotaTeq
Slide: K Neuzil, PATH
Current Status of Rotavirus Vaccine Introduction
Rotavirus Vaccine Experience to Date
11Borrowed from: http://dannybrown.me/wp-content/uploads/2011/01/success_baby.jpg (Courtsey of U Parashar)
12
Issues of safety ORVs- (real or implied) remain! Post-Licensure Data
Source: www.cdc.gov/vaccines/acip/meetings
RV1 RV5
Australia 5.0 5.9
Mexico 1.2
USA 5.3 0.5-1.5
Intussusception cases /100,000 vaccinees
Other safety issues: PCV, antigenemia, AGE
RV Vaccines Need a Separate Cold ChainCost and Volume Comparison with Existing Vaccines
US$4,687.50 *US$4,687.50 *
625 dosesof rotavirus vaccine.
District vaccine store, Brazil.
625 dosesof rotavirus vaccine.
District vaccine store, Brazil.
4,100 dosesof polio and measles
vaccines. Rural hospital storage,
Mozambique.
4,100 dosesof polio and measles
vaccines. Rural hospital storage,
Mozambique.
US$635.50US$635.50
*Older photo—improvements in packaging volume have been achieved. Courtesy: Darin Zehrung
Rotarix* & RotaTeq† Efficacy vs Social Economic Status
Nelson & Glass, Lancet 2010
▲Bangladesh*
▲China*
Risk Factors for Lower Performance Of Live Oral Rotavirus Vaccine
Factors that lower viral titer
• Breast milk
• Maternal antibodies
• Stomach acid
• Prior exposure
Factors that impair immune
response• Malnutrition - Zn, Vit A
• Interfering microbes- viruses and bacteria
• Other infections- HIV, malaria, TBC
Others: Novel & diverse strains
Host genetic diversity
Studies to improve efficacy of ORVs
• Transplacentally transferred maternal serum Ab - Change schedule: time & no. of doses - S. Africa, Pakistan, Bangladesh, India
• High levels of Ab in breast milk- Withhold breast feeding at time of vaccination- S. Africa, India, Pakistan, Bangladesh, Nicaragua
● Add Nutritional supplements - zinc, vitamin A, probiotics, etc.- India, Pakistan
• Increase Rotarix titer ?
• Search for RV vaccine -- OPV interference - South Africa, Bangladesh
None has led to major improvement !
Inactivated Rotavirus vaccine (IRV)
Efficacy ▪ Not subject to interference/gut enteropathy seen with oral vaccines▪ more effective for infants in low income countries
Safety▪ No stigma of ORVs - intussusception, PCVs▪ No vaccine-acquired disease or new reassortant virulent strain
Combination vaccines – ease delivery, lower administration cost, increase vaccine coverage
Technology well established/tested (e.g., IPV, HAV)
Would represent insurance against problems with ORVs
IRV could be a Game Changer !
CDC-9 as a monovalent IRV candidate
G1P8G1P8 G2P4G2P4
G1P8 G1P8
● 107 ~ 108 titer in Vero cells
● Predominant (>90%) triple-layered
● Stable during USP & DSP
ffu
/ml
IRV: Strain & dose matter !
Jiang et al, Human Vaccines & Immunotherapeutics 2013
1. Three doses induce cross neut. antibodies to human strains & reassortant G1 strain
2. Little cross reactivity with animal strain or reassortant P8 strain
-------------- ---------------------------------------------------------------------------------Homotypic Heterotypic
Wang et al Vaccine 2010
Vaccine
Placebo
Neutralizing antibody (post dose 3)
Proof of concept for IRV in gnotobiotic piglets
Skin Immunization
● One of the earliest known route of vaccination -- smallpox, TB
● Immunology: rich in APC – Langerhans cells & dermal DC
● No hypodermic needle, no disposal of sharp waste
● No pain
● Combination vaccines, mass vaccination campaigns
● No need for additional cold chain
22 of 53
←Vaccinostyle←Rotary lancet←Surgical needle
Source: Fenner, et al, WHO, 1988
“Multiple Pressure” method
Smallpox Delivery TechniquesEarly Tools for Breaking the Skin
0
1000
2000
3000
4000
5000
6000
7000
IgG
tite
r (G
MT)
MN 5 µg
MN 0.5 µg
IM 5 µg
IM 0.5 µg
IM dis 5 µg
MN mock
0 10 28
Days Post Inoculation
Skin immunization uses fractional doses and enhances antibody response in mice
Moon et al, Vaccine, 2013 (in collaboration with M. Prausnitz)
Dose sparing: 10% MN = 100% IM
Beforecoating
Aftercoating
NanoPass developed MicronJet™, an intradermal (ID) microneedles device
Used for ID delivery of vaccines and large molecules
First true (~0.5mm) microneedle device ever registered with FDA
Microneedles are barely visible to the naked eye
Clinically shown to be almost painless and non-intimidating
Applicable for adults and pediatrics (i.e., IPV)
NanoPass MicronJet™
IntanzaNanoPass
Courtesy: Yotam Levin
Dose sparing effect established
Jiang (unpublished data)
1st Vax 2nd Vax 3rd Vax 1st Vax 2nd Vax 3rd Vax
ID & IM immunization induces comparable IgG & IgA titers in gnotobiotic piglets
ID: 5 ug Ag; IM: 5 ug Ag + 600 ug Al(OH)3; Control: diluent
IRV induces protection against oral challenge in piglets
Jiang (unpublished data)
IRV (ID)Placebo (ID) IRV (IM)
RV shedding in stool was measured by EIA
Day after oral challenge
RV
an
tig
en
in
sto
ol
(OD
va
lue
)
CDC IRV Program – Current status
Established technology (cell substrate, methods, assays, etc.) Strains developed, characterized
- CDC-9 G1P8
Inactivation method - Heat process – simple, robust, maintain structural integrity- Formalin procedure
Process development, formulation, stability Pre-clinical studies
- Proof of concept for serum antibody in macaques- Proof of concept for IRV by IM immunization in mice, guinea pigs & piglets- Proof of concept for IRV by skin immunization in mice & piglets
IP protection (strains & inactivation method) Partnerships (CMO, manufacturers, NGO, etc)
Discovery to Market: IRV Pre-clinical Studies
Clinical trials
▪ cGMP MVB production complete (CMO)
▪ SBIR contracts (CMO)
• Phase I: Optimization of rotavirus vaccine production (complete)
- USP & DSP process development
- Assay development
• Phase II: Preparation of IRV pilot lots for phase I clinical trials
- Validation of processes, scale-up, inactivation & formulation
- Toxicity study in animals
- cGMP production of pilot vaccine lots
▪ 2011 Winner - CDC’s inaugural innovation Fund Challenge▪ 2011 Excellence in Technology Transfer Award - SE Federal Laboratory Consortium▪ 2012 Excellence in Technology Transfer Award - Federal Laboratory Consortium▪ 2013 CDC SBIR Phase I Award▪ 2014 CDC SBIR Phase II Award
Public Support & Public-Private Partnerships
CDC Commercial Partners#
Co
mp
an
y
Pathways Forward
Early Phase (5~7 yrs): Develop stand-alone IRV (IM & ID)
- Demonstrate safety, efficacy, and value
- Determine if IRV is more effective than ORV
Late Phase (3-5 yrs): Combine IRV with multivalent vaccine
(e.g., DTaP, IPV) for IM administration (established vaccine Co.)
- Adds competitive value to multivalent vaccine
- Avoids administration & delivery costs
- Opens up product to global market
Or Combine with target vaccine (e.g., IPV) for ID administration
(Biotech Co.)
In partnerships with several vaccine manufacturers
OPV
IPV then OPV
IPV
Countries Currently Using IPV in National Immunization Programs
Courtesy: Cara Burns
The global move to IPV !
AcknowledgmentsAcknowledgmentsCDC
Yuhuan Wang
Sung-Sil Moon
Daniel Velasquez
Houping Wang
Mathew Esona
Jennifer Hull
Charles Humphrey
Lauren Snipes
Larry Westerman
Umesh Parashar
Jon Gentsch
Roger Glass
Outside CDC
Linda Saif
Anastasia Vlasova
Marli Azevedo
Mark Prausnitz
Chris Edens
Yotam Levin
Penelope Dennehy
Harry Keyserling
Jean-Francois Saluzzo
Stan Cryz
Harry Greenberg
Vic Van Cleave
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