Typhoid conjugate vaccines in India - Aug 2015

Typhoid Conjugate VaccinesOpportunities & Challenges

Dr Gaurav Gupta

Conflict of Interest

• Received grants from various vaccine manufacturers including – Sanofi Pasteur– GSK– Abbott– Novartis

Scope

• Is typhoid a serious health problem in India?• Are there any issues in the current

Polysaccharide vaccine?• Is the Conjugate Vaccine better?• Recommendations & FAQs

Age stratified disease burden

Crump JA, et al. Bull World Health Organ 2004;82:346-353

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Age groups

Lab DiagnosisMicrobiological procedure: Blood Cultures

• Bacteremia occurs early in the disease

• Blood Cultures are positive in – 1st week in 90%– 2nd week in 75%– 3rd week in 60%– 4th week & later in 25%

Source: Asma Ismail. New Advances in the Diagnosis of Typhoid and Detection of Typhoid Carriers. Malays J Med Sci. 2000 Jul; 7(2): 3–8.

Serological procedure: Felix-Widal Test

Significant titers helps in Diagnosis• Serum agglutinins raise abruptly during the

2nd or 3rd week

• Following Titers of antibodies against the antigens are significant when single sample is tested

O > 1 in 160 H > 1 in 320

• Testing a paired sample (7-10 days) for raise of antibodies carries a greater significance

Limitations of Widal test4 fold rise of antibody in paired sera is considered diagnostic of typhoid fever

Paired sera are often difficult to obtain and

Specific chemotherapy has to be instituted on the basis of a single Widal test

False Positive reactions may occur

Source: Zorgani A, Ziglam H. Typhoid fever: misuse of Widal test in Libya. J Infect Dev Ctries. 2014 Jun 11;8(6):680-7. 2. Asma Ismail. New Advances in the Diagnosis of Typhoid and Detection of Typhoid Carriers. Malays J Med Sci. 2000 Jul; 7(2): 3–8.

Newer diagnostic tests2

IDL Tubex, Typhidot test, Typhidot-M , Typhidot rapid and IgM dipstick test

MDR typhoid fever (MDRTF) in the last 15 yrs: India

• Incidence of MDRTF: Increased from 34% in 1999 to 66% in 2005• Mortality during MDRTF epidemics: 7% to 16% (much higher than seen in susceptible typhoid

fever, 2%)• Increased incidence of complications

Source: Zaki SA, Karande S. Multidrug-resistant typhoid fever: a review. J Infect Dev Ctries. 2011 May 28;5(5):324-37.

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How can Typhoid be avoided?

• Avoid risky foods or drinks

• Use only clean water

• Ask for drinks without ice unless you know where it’s coming from

• Only eat foods that have been thoroughly cooked

• Avoid raw fruits and vegetables

• Get vaccinated

Source: http://www.cdc.gov/nczved/divisions/dfbmd/diseases/typhoid_fever/#avoidance as accessed on 28 Jan 2015, 5:47 pm

Very difficult in developing country like India

http://www.cdc.gov/nczved/divisions/dfbmd/diseases/typhoid_fever/

Scope

• Is typhoid a serious health problem in India?• Are there any issues in the current Polysaccharide vaccine?• Is the Conjugate Vaccine better?• Recommendations & FAQs

Generation: Inactivated Whole Cell Vaccine1st Generation: Cell Vaccine (Live Oral)2nd

Generation: Vi Polysaccharide Vaccine2nd

Generation: Vi Polysaccharide Conjugate Vaccine3rd NTS & Paratyphi Conjugate Vaccine4th

Different types of Typhoid vaccines

New generation

Typhoid vaccine

Parenteral

Vi-polysaccharide (Vi-PS)

Vi-Polysaccharide Conjugate vaccines

Conjugated with Pseudomonas

aeruginosa exotoxin A (not available in

India)

Conjugated with Tetanus Toxoid

Oral (Not available in India)

Source: Ajay Kalra, Vipin M. Vashishtha. 3.11 TYPHOID VACCINES. IAP Guidebook on Immunization 2013–14. page no 257-270

New generation typhoid vaccines

Vi-capsular polysaccharide vaccine

• Contains highly purified antigenic fraction of Vi-capsular polysaccharide antigen of S. typhi.

• Each dose contains 25 μg of purified polysaccharide for IM or subcut use• Should be stored at 2–8oC

Since it is a pure polysaccharide vaccine, • Poorly Immunogenic < 2 years• No Booster Effect• Poor Quality Antibodies• Hyporesponsiveness to repeat doses• Lower efficacy


Polysaccharide Vaccines Concern 3Limited efficacy (Evidence 1)

• Single dose of typhoid polysaccharide vaccine given• Subjects were then followed for 2 years• Overall level of protection among all residents of Vi vaccine clusters was 57%

Source: Sur D et al. A cluster-randomized effectiveness trial of Vi typhoid vaccine in India. N Engl J Med. 2009 Jul 23;361(4):335-44.

• Single dose of Vi polysaccharide vaccine prevents – Year 1: Efficacy 69%– Year 2: Efficacy 59%– Year 3: Cumulative

efficacy of the vaccine is around 55%

Polysaccharide Vaccines Concern 3Limited efficacy (Evidence 2)

Source: Anwar E, Goldberg E, Fraser A, Acosta CJ, Paul M, Leibovici L. Vaccines for preventing typhoid fever. Cochrane Database Syst Rev. 2014 Jan 2;1:CD001261

This data clearly suggests moderate efficacy of typhoid polysaccharide

vaccines

Polysaccharide vaccine leads to lower antibody response to revaccination where repeated doses of the vaccine seem to induce a state of immune

Hyporesponsiveness

Polysaccharide Vaccines Concern 4Hyporesponsiveness

Source: http://whqlibdoc.who.int/hq/2012/WHO_IVB_12.02_eng.pdf

These are important considerations when developing an immunization strategy to use Vi polysaccharide vaccine

WHOReport of the Ad-hoc consultation on typhoid

vaccine introduction and typhoid surveillance - 2012

IAP comments 2013-2014

Conjugation of the Vi antigen with a protein carrier is hence desirable

as it would induce a T cell dependent immune response


Scope


Source: Klouwen berg and Bont Neonatal and infantile immune responses to encapsulated bacteria and conjugate vaccines. Clin Dev Immunol.2008; 2008:628963.

New generation

Typhoid vaccine

Parenteral





India)





Typhoid Conjugate vaccine: Vi- rEPA vaccine

• Developed by US NIH (John Robbins & Colleagues)• Capsular polysaccharide of Salmonella typhi

(Vi) is bound to the recombinant exoprotein A (rEPA) of Pseudomonas aeruginosa

Vi-PS Conjugate vaccine with Pseudomonas aeruginosa exotoxin A

• In a double-blind, randomized trial • Evaluated the safety, immunogenicity & efficacy of the Vi-rEPA vaccine in children 2 to 5 yrs

old in Vietnam

• Each of the subject received two inj 6 wks apart of either Vi-rEPA or a saline placebo

• Efficacy: 91.5%

Source: Lin FY et al. The efficacy of a Salmonella typhi Vi conjugate vaccine in two-to-five-year-old children. N Engl J Med. 2001 Apr 26;344(17):1263-9.

Vi-PS Conjugate vaccine with Pseudomonas aeruginosa exotoxin A

• 4 wks after the 2nd inj of the vaccine, serum IgG Vi antibodies had increased by a factor of 10 or more

• Overall efficacy after 27 mths of active surveillance followed by 19 mths of passive surveillance was 89%

• No serious adverse reactions were observed

Not available in India

Source: Lin FY et al. The efficacy of a Salmonella typhi Vi conjugate vaccine in two-to-five-year-old children. N Engl J Med. 2001 Apr 26;344(17):1263-9.

Phase III Trial – Clinical Effectiveness

• S. typhi was isolated from 4 of the 5525 children who were fully vaccinated with Vi-rEPA V/s 47 of the 5566 children who received both injections of placebo (efficacy, 91.5 percent)

• Among the 771 children who received only one injection, there was 1 case of typhoid in the vaccine group V/s 8 cases in the placebo group.

New generation

Typhoid vaccine

Parenteral





India)






(25mcg)


(5 mcg)

• Based on a large efficacy study, VI-rEPA has been shown to be

protective for 4 years and Ab titres protective over 8 years in 2-5 year age

group and 10 years in adults1

• Based on data from the Vi-rEPA studies, an anti-Vi IgG titer 2.0 µg/ml is

a suggested estimate of protective titer2.

• In the absence of an internationally accepted Vi IgG standard serum, this

is the best correlate for protective efficacy, currently available.

Efficacy – correlate of protection

1. Szu S Expert Rev. Vaccines 2013.12(11):1273-1286.2. Szu S, et al. Vaccine 2014. 32 (20): 2359-2363.

Dose schedule

Vi-rEPA, 25µg Vi per dose

Szu S Expert Rev. Vaccines 2013.12(11):1273-1286.Mohan VK, et al. Clin Infect Dis. 2015 Apr 13. [Epub ahead of print]

Typbar-TCV, 25µg Vi per dose

• Single dose schedule of 25µg Vi-rEPA, as immunogenic as two doses, over

30+ months of follow up.

• Single dose of 25µg Typbar-TCV; immunogenic over 2 years of follow up in

ages 6 months – 45 years (3 year follow-up data under analysis).

Protective level

Szu S Expert Rev. Vaccines 2013.12(11):1273-1286.Mohan VK, et al. Clin Infect Dis. 2015 Apr 13. [Epub ahead of print]

Comparative immunogenicity

Anti-Vi antibodies persist over the protective titers for upwards of 4 years aftervaccination

Protectivelevel

Study investigators and sites

• Dr. Monjori Mitra, Institute of Child Health, Kolkata

• Dr. G. Sampath, Institute of Preventive Medicine, Hyderabad.

• Dr. P. Venugopal, King George Hospital, Visakhapatnam.

• Dr. Mukesh Gupta, Soumya Child Clinic, Jaipur

• Dr. Sudhakar, Priya Children’s Hospital, Vijayawada

• Dr. S.N. Mahantashetti, JNMC-WMKS, Belgaum

• Dr. Sri Krishna, Mahavir Hospital, Hyderabad

• Dr. Bhuvaneswar Rao, Sri Srinivasa Children’s Hospital, Vijayawada

Cohort Age groupTreatment

Groups Enrolled Completed Drop outTest Ref

I≥6 months to ≤2 years

(Single Arm – Open label) 327 - 327 307 20

II>2 years to ≤45 years

(Two arm – Double blind) 340 314 654 637 17

Phase III Study: Study design & study population

• Study Design: Randomized, multicentric, controlled Phase III study • Study Population: Healthy subjects divided in to 2 groups of ≥6 mths to ≤2

yrs, & >2 yrs to ≤45 yrs• Randomization and labeling done by third party• 981 subjects allocated to test vaccine and reference vaccine across all the

centers

31Source: V Krishna Mohan, Vineeth Varanasi, Anit Singh, Marcela F Pasetti, Myron M Levine, R Venkatesan, and Krishna M Ella. Safety and immunogenicity of a Vi polysaccharide-Tetanus Toxoid conjugate vaccine in healthy infants, children and adults in typhoid endemic areas: a multi-center, two-cohort (open-label/double-blind, randomized, controlled), phase III study. Clin Infect Dis. (2015) First published online: April 13, 2015

Phase III Study: Results(Advantages)

(Cohort I, ≥6 mths to ≤ 2 yrs)

Superior seroconversion is observed in ≥6 mths to ≤ 2 yrs,

thus establishes the immunogenicity of typhoid

conjugate vaccine in ≥6 mths to ≤ 2 yrs

Day 42 Day 7200.00%

20.00%

40.00%

60.00%

80.00%

100.00%

120.00%

98.10%

59.50%

% o

f sub

ject

s

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Long term immunogenicity (Seroconversion %, 4-Fold Rise) in ≥ 6 months to < 2 yrs

Source: V Krishna Mohan, Vineeth Varanasi, Anit Singh, Marcela F Pasetti, Myron M Levine, R Venkatesan, and Krishna M Ella. Safety and immunogenicity of a Vi polysaccharide-Tetanus Toxoid conjugate vaccine in healthy infants, children and adults in typhoid endemic areas: a multi-center, two-cohort (open-label/double-blind, randomized, controlled), phase III study. Clin Infect Dis. (2015) First published online: April 13, 2015


Conjugate polysaccha-ride

Polysaccharide0.00%

20.00%

40.00%

60.00%

80.00%

100.00%

120.00%

97.30%93.10%

74.10%

53.30% Day 42Day 720

% o

f sub

ject

s

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Long term immunogenicity (Seroconversion %, 4-Fold Rise) in ≥ 2 yrs to ≤ 45 yrs

(Cohort II, > 2 yrs to ≤ 45 yrs)

Seroconversion rates were significantly higher in conjugate

polysaccharide vaccine compared to polysaccharide

vaccine at 720 days



Study groupGMTs/n

Day 0 Day 42 Day 540 Day 720 Day 42 after booster dose

Conjugate polysaccharide Cohort I 9.45/307 1937.4/307 58.63/122 48.28/220 1721.9/187

Conjugate polysaccharide Cohort II 10.4/332 1292.5/332 92.81/212 81.7/243 1685.3/175

Polysaccharide Cohort II 11.6/305 411.1/305 51.7/194 45.8/197 445.6/57

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Booster dose effect


Shows excellent booster effect suggesting

immunological memory of conjugate vaccine

No difference in the GMTs after revaccination

suggesting Hyporesponsiveness with Polysaccharide vaccines

• Avidity index, avidity maturation and immunoglobulin G (IgG) isotype switching of antibodies after vaccination are evaluated as indicators of protective immunity.

• Also serve as an indicator for successful priming by induction of immunological memory, as shown by typhoid conjugate vaccines (ie. Enteroshield).2,3

Avidity index & Its role

Perciani CT, et al. Improved method to calculate the antibody avidity index. J Clin Lab Anal. 2007;21(3):201-6. 2) Goldblatt D, Pinto Vaz AR, Miller E. Antibody avidity as a surrogate marker of successful priming by Haemophilus influenzae type b conjugate vaccines following infant immunization. J Infect Dis. 1998;177:1112-5. 3) Mohan VK, et al. Safety and Immunogenicity of a Vi Polysaccharide-Tetanus Toxoid Conjugate Vaccine (Typbar-TCV) in Healthy Infants, Children, and Adults in Typhoid Endemic Areas: A Multicenter, 2-Cohort, Open-Label, Double-Blind, Randomized Controlled Phase 3 Study. Clin Infect Dis. 2015 Apr 13. pii: civ295.

Antibody avidity: Overall binding strength of an antibody to an antigen.1

Affinity refers to the strength of a single antibody-antigen interaction. Each IgG antigen binding site typically has high affinity for its target.

Avidity refers to the strength of all interactions combined. IgM typically has low affinity antigen binding sites, but there are ten of them, so avidity is high.

Phase III Study: Avidity Index(Advantages)

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Conjugate polysaccharide vaccine induced higher avidity antibodies compared to polysaccharide vaccine, 720 days post-immunization & after the booster dose

Conjugate polysaccharide

Conjugate polysaccharide

Polysaccharide


Phase III Study: Results (Safety)

Events Occurred AEs (%)

Fever 10

Pain at Injection site 3.7

Redness at injection site 0.3

Vomiting 0.3

Cough 0.6

Cold 0.6

Itching 0.3

LRTI 0.3

Diarrhoea 0.3

Malaise 0.3

Myalgia 0.3

Events Occurred Test GroupAEs n(%)

Reference Group

AEs n(%)p-value

Fever 14 (4.28) 9(2.75) 0.5245

Arthralgia 1(0.3) 1(0.3) 1.0000

Pain at Injection site 12(3.6) 8(2.6) 0.5057

Swelling 5(1.53) 1(0.3) 0.2194

Itching 1(0.3) 0

Tenderness 2(0.61) 0

Nausea 0 2(0.6)

Weakness 0 1(0.3)

Cold 0 1(0.3)

Myalgia 0 1(0.3)

Cohort - II

Adverse events were uncommon & occurred with similar rates in both the groups

37Source: V Krishna Mohan, Vineeth Varanasi, Anit Singh, Marcela F Pasetti, Myron M Levine, R Venkatesan, and Krishna M Ella. Safety and immunogenicity of a Vi polysaccharide-Tetanus Toxoid conjugate vaccine in healthy infants, children and adults in typhoid endemic areas: a multi-center, two-cohort (open-label/double-blind, randomized, controlled), phase III study. Clin Infect Dis. (2015) First published online: April 13, 2015

Cohort - I

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Phase III clinical study: Conclusion

Efficacy

Safety

• Statistically significant difference between test & reference vaccine in terms of GMT and 4 fold seroconversion (p<0.05)

• Induces high Ab titres in children < 2 yrs age• Proves superiority of conjugate vaccine over polysaccharide

Conjugate polysaccharide vaccine is safe & more effective than polysaccharide vaccine in Indian population

Single dose of typhoid conjugate vaccine is well-tolerated, induces robust and long lasting immune response


Scope


Whom to Vaccinate?Recommendations

• Recommends the new Vi-PS conjugate vaccine < 1 yr of age, preferably between 9-12 mths (min age 6 mths)

• Recommends for routine use

Indian Academy of Pediatrics

(IAP)

• Basic action can protect you from typhoid fever: Get vaccinated against typhoid fever

Centers for Disease Control and prevention

(CDC)

• For people travelling in high-risk areas where the disease is endemic. People living in such areas, people in refugee camps, microbiologists, sewage workers and children should be the target groups for vaccination

World Health Organization

(WHO)

Source: http://www.cdc.gov/nczved/divisions/dfbmd/diseases/typhoid_fever/ as accessed on 18 Feb 2015, 9:35 pm. http://www.who.int/wer/2008/wer8306.pdf?ua=1 as accessed on 18 Feb 2015, 9:41 pm. http://www.indianpediatrics.net/dec2013/1095.pdf as accessed on 18 Feb 2015, 9:58 pm

http://www.cdc.gov/nczved/divisions/dfbmd/diseases/typhoid_fever/

http://www.who.int/wer/2008/wer8306.pdf?ua=1

http://www.indianpediatrics.net/dec2013/1095.pdf

• Field efficacy data• Cost of recommended TCV• Need for Booster(s)• International data / use

Challenges remaining

1. Target age group for TCV immunization in the UIP program

• Primarily from 6 months age and above.

2. Number of vaccine doses in primary vaccination series

• Single dose schedule.

3. Timing of booster dose

• Spaced by at least 6 months from first vaccine dose.

• If missed, booster dose can be given up to 3 years age.

• School based booster program can also be considered.

Conclusions (1)

5. Immunological basis of protection, correlates of protection

• Current guidance available based on NIH Efficacy studies.

• Anti-Vi IgG, internationally accepted standard needed.

6. Persistence of protective levels of antibodies

• Typbar-TCV is able to protect for 3 years (current data).

7. Compatibility with measles vaccine

Typbar-TCV found to be compatible with Measles

containing vaccines.

Conclusions (2)

• How effective is the TCV vaccine?• With a single dose how long would TCV remain effective?• With 2 doses appropriately spaced, how long would TCV remain

effective?• Is the claimed efficacy different for vaccination < 2 years and above

2 years?• Has hyporesponsiveness been confirmed in clinical data for

Typhoid polysaccharide vaccine?• Which TCV should be used ?

FAQs

• What is the claimed efficacy of the TCV vaccine?• Regarding the long term protection associated with typhoid

conjugate vaccines, the published literature states that the immunity persisted for more than 8 years. (Szu SC. Development of Vi conjugate - a new generation of typhoid vaccine. Expert Rev Vaccines. 2013 Nov;12(11):1273-86)

FAQs

• As per immunogenicity data available, what is the perceived efficacy of TCV and how does that compare with the clinical efficacy of currently available Polysaccharide vaccines?

• Correlate of protection is considered to be > 2mcg in the study. And data suggest that more than 90% of the subjects were above > 2mcg levels. So we can expect the efficacy of this conjugate vaccine approx 90 % which is similar to that of published studies on other typhoid conjugate vaccines

FAQs

• How long does the protection last after only 1 dose of TCV - if the second dose is not taken - your best guess?

• Approximately 2.5 to 3 years. As per the published study, 720 days (2 yrs) data after 1st dose is there. GMTs at 720 days are approx 8-10 folds more than the baseline. This 8-10 folds may give additional protection up to 6 months to 1 yr.

FAQs

• Also what is the likely duration of protection when 2 doses have been given as suggested?

• Regarding the long term protection associated with typhoid conjugate vaccines, the published literature states that the immunity persisted for more than 8 years. (Szu SC. Development of Vi conjugate - a new generation of typhoid vaccine. Expert Rev Vaccines. 2013 Nov;12(11):1273-86)

FAQs

• Is the claimed efficacy different for vaccination < 2 years and above 2 years?

• As per the immunogenicity study the immune response in cohort I (> 6 months to < 2 years) was 160 folds higher from the baseline and in cohort II (>2 years < 45yrs) it was 180 folds higher than the baseline titers. This data suggests the robust immune response of typhoid conjugate vaccines in all the age groups included in the study. (Mohan VK et al. Safety and Immunogenicity of a Vi Polysaccharide-Tetanus Toxoid Conjugate Vaccine in Healthy Infants, Children, and Adults in Typhoid Endemic Areas: A Multicenter, 2-Cohort, Open-Label, Double-Blind, Randomized Controlled Phase 3 Study. Clin Infect Dis. 2015 Aug 1;61(3):393-402)

FAQs

• Has hyporesponsiveness been confirmed in clinical data for Typhoid polysaccharide vaccine?

• GMTs in the polysaccharide group at 42 day was 411 and after the revaccination it was 445. So after giving the repeated dose of polysaccharide vaccine, the immune response was almost similar to that of 42 days after the 1st dose. However various published literature suggests that there is a possibility of hyporesponsiveness with repeated dosing of typhoid polysaccharide vaccines. (Mohan VK et al. Safety and Immunogenicity of a Vi Polysaccharide-Tetanus Toxoid Conjugate Vaccine in Healthy Infants, Children, and Adults in Typhoid Endemic Areas: A Multicenter, 2-Cohort, Open-Label, Double-Blind, Randomized Controlled Phase 3 Study. Clin Infect Dis. 2015 Aug 1;61(3):393-402)

FAQs

• What is the protective titre correlates for Typhoid disease?• Unlike many vaccine preventable diseases, serologic correlates of

protection are not available for typhoid disease or typhoid vaccines (http://medind.nic.in/ibv/t09/i2/ibvt09i2p181.pdf )

• We assessed the proportion of subjects whose titers remained ≥2 μg/mL the proposed protective threshold and the same has been used in other typhoid conjugate vaccine clinical study by Dr Szu et al.(Mohan VK et al. Safety and Immunogenicity of a Vi Polysaccharide-Tetanus Toxoid Conjugate Vaccine in Healthy Infants, Children, and Adults in Typhoid Endemic Areas: A Multicenter, 2-Cohort, Open-Label, Double-Blind, Randomized Controlled Phase 3 Study. Clin Infect Dis. 2015 Aug 1;61(3):393-402)

FAQs

http://medind.nic.in/ibv/t09/i2/ibvt09i2p181.pdf

• Any reports of culture / serology positive typhoid cases after TCV vaccines - a pediatrician here has seen 3-4 culture positive cases after this vaccine?

• We have launched this typhoid conjugate vaccine in the month of June 2015. So in these 2 months no report has come regarding the seropositive typhoid case.

FAQs

• Any suggestions by IAP/ the company regarding need for boosters after the second dose - say 10 years ?

• No comments by IAP regarding the 2nd booster

FAQs

• How long does the protection last after only 1 dose of TCV - if the second dose is not taken - your best guess?

• Approximately 2.5 to 3 years.

FAQs

Typhoid conjugate vaccines in India - Aug 2015

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