Preventing Invasive meningococcal disease in < 2 year children in India. Use of MCV 4 (Menactra). Chandigarh March 2018. Incidence of IMD in India, and safety and efficacy of MCV4 vaccination

1. Preventing IMD in < 2 yr in India
Dr. Gaurav Gupta,
28th March, 2018, Chandigarh

2. • Conflict of Interest

3. Questions
• Do we really need a Menigococcal vaccine?
• Is Meningococcal a problem in this age group?
In India?
• Is the vaccine safe & effective in this age
group?
• Best schedule/ recommendations?
• Need for boosters?

4. Meningococcal SG Distribution Varies Geographically
NG=nongroupable.
1Public Health Agency of Canada. Online; 2 EU-IBIS. Online; 3Lin. Zhongguo Ji Hua Mian Yi. 2009;15(1); 4 CDC. Online;
5Organizacion Panamericana de Salud. Informe Regional de SIREVA II, 2012; 6WHO Regional Office for Africa. MDSC meningitis
weekly bulletin. 2009;Week 27-31; 7Sinclair. Trop Med Int Health. 2010;15(12); 8Infectious Disease Surveillance Center. IASR.
2005;26(2):; 9 NICD. Communicable Diseases Surveillance Bulletin. 2009;7(1) 10The Australian Meningococcal Surveillance
Programme. Commun Dis Intell. 2009;33(1). 16Memish et al. Euro Surveill. 2013;37(12)

5. Invasive Meningococcal Disease Is Difficult to
Diagnose and Rapidly Lethal
• Flu-like nature of early symptoms makes a definitive diagnosis
challenging1
• Rapid progression, with death in as little as 24 hours1,2
1Thompson et al. Lancet. 2006;367(9508); 2Branco et al. J Pediatr (Rio J). 2007;83(2 suppl)
12–15 Hours1,2
Characteristic
15–~24 Hours1,2
Late
4–8 Hours1,2
Nonspecific
Fever, irritability, nausea
or vomiting, drowsiness,
poor appetite, sore throat,
coryza, general aches
Hemorrhagic rash,
neck stiffness,
photophobia
Confusion or delirium,
seizure,
unconsciousness;
possible death
Hospital admission at median of ~19 hours1

6. High mortality in children <1yr & <4 y of age
Argentina 2000 - 2013
Source : SNVS. INEI- ANLIS. Malbrán. DiNaCEI, Ministerio de Salud de
la Nación

7. Globally IMD Incidence is High Under 5y of AgeUnitedStates1,
1998–2007
Canada3,2015
EU/EEA2,2012Argentina4,2014
5.38
1.47
0.9
0.42 0.3
0.74 0.76
0.28
0.69
0
1
2
3
4
5
6
<1 1 2–4 5–9 10–13 14–1718–24 25–64 ≥65
0
0.5
1
1.5
2
2.5
3
3.5
< 1 1-4 5-9 10-1415-1920-2425-2930-3940-59 60+
Male
Female
0.00
2.00
4.00
6.00
8.00
10.00
12.00
14.00
16.00
< 1 1-4 5-9 10-1415-1920-2425-3435-4445-64 >65
1. Cohn et al. Clinical Infectious Diseases 2010; 50:184–91. 2. ECDC SURVEILLANCE REPORT. Annual
epidemiological report 2014 –Available from: https://ecdc.europa.eu. 3. Available from
http://diseases.canada.ca/notifiable/charts?c=abs 4. Source : SNVS. INEI- ANLIS. Malbrán. DiNaCEI, Ministerio
de Salud de la Nación

8. Infants remain susceptible to IMD due to the
reduced level of Maternal antibodies
Number of cases / 100,000 population of specific age, 1965
% Serum at each age with activity Serum bactericide ≥1: 4
against C11 strains (Serogroup C) *
Goldschneider I, et al. J Exp Med. 1969;129:1307-1326.
*SimilarresultswereobservedforstrainsA1(serogroupA)and
B11(serogroupB)
Months Years

9. Indian scenario – IMD surveillance
During Inter-epidemic periods
• Central Bureau of Health Intelligence (CBHI) – NHP report
• Integrated Disease Surveillance Project (IDSP)
• Scattered individual reporting through publications/ reports by hospitals/
laboratories
During Epidemics
• Laboratory based: Situations where reasonably good lab Infrastructure (Delhi,
Meghalaya)
• Hospital based : Lab structure not adequate, Adequate hospital facillities
(Meghalaya, Tripura)
• Community based : In case both labs and hospital facillity inadequate eg In Tripura

10. India has seen outbreaks of Meningococcal
meningitis every 6-8 yrs in several states
East West North Central South
Probable
Cases
Deaths
1961–62 Delhi UT* 27 2
1966–67 New Delhi 616 129
1968–69
Andhra
Pradesh* 47 2
1969 Maharashtra* 10 1
1985–88 New Delhi 6133 799
1985
Assam (25),
Tripura (2),
Sikkim (55),
West Bengal
(471)
Gujarat (195),
Maharashtra
(1573), Goa
Daman & Diu
(30)
Bihar (37),
Haryana(20), Uttar
Pradesh (334)
Madhya
Pradesh (32),
Rajasthan
(473)
Karnataka(25),
Tamil Nadu
(22)
1985 ⁄ 87 Gujarat 197 34
1989 Orissa 119 89
1997 Chandigarh* 8 4
2005–08 New Delhi 867
2008 Meghalaya 2000 200
2009 Tripura 200 50
Outbreaks predominantly by meningococci serogroup A
*Isolated outbreak
D. Sinclair et al. Tropical Medicine and International Health. volume 15 no 12 pp 1421–1435
December 2010

11. IMD is a notifiable disease in India
National Health Profile data (2016)
Integrated Disease Surveillance
Programme
2012 2013 2014 2015 2016
1 Bihar 260 765 1042 1226 905
2 West Bengal 2279 667 754 944 899
3 Madhya Pradesh 141 614 145 84 266
4 Karnataka 104 237 159 281 207
5 Orissa 615 244 183 355 154
6 Uttarakhand 70 110 138 82 92
7 Maharashtra 1125 161 524 334 89
8 Uttar Pradesh 48 39 19 166 84
9 Rajasthan 2 15 189 212 73
10 Chandigarh 31 100 12 61 61
11 Delhi 119 73 61 34 61
12 Mizoram 38 9 34 12 47
13 Jharkhand 29 81 36 95 34
14 Haryana 4 15 6 150 32
15 Andhra Pradesh 268 189 74 86 30
TOTAL 5609 3821 4215 4122 3034
By Central Bureau of Health Intelligence
(CBHI), DGHS, Ministry of Health & Family
Welfare, GOI
Year
No cases
of
Meningitis
as per P
form
No +ve for MM as per L form
2011 12600 170
2012 12400 182
2013 14474 195
2014 13826
553(126 from Bihar,99 from MP,
95 Maharashtra)
2015 14590
992 [ 328 (Bihar),191 (MP)
190(UP),48
(Maharashtra),39(Assam)
32(Haryana), 29(Raj), 28
(Karnataka) ]
By NCDC (Launched in Nov. 2004 with World
Bank Assistance)
National Health Profile , India 2012-2016, Central Bureau of Health Intelligence. Available at
http://cbhidghs.nic.in
Dr Sunil Gupta (NCDC) . Meningococcal disease. Presented at PEDICON Jan 2017

12. Fig. Distribution of N. meningitides cases according to ageFig. Distribution of meningitis pathogens according to age
• Retrospective data collection from 1 January 2007 to 31 December 2013 (7 years)
• 2 months to 8 years old children admitted for bacterial meningitis confirmed by culture of CSF
Bankura Medical College, West Bengal (2007-13)
SK Roy et al. JMSCR Volume 2, Issue 12, Page 3525-3533, December-2014

13. JNMCH, Aligarh (2011)
• Study from June 2001 to June 2009 (8 y)
• 403 samples were positive on culture
• 83.8% were <12 years of age, maximum
147 (36.7%) were infants.
0
10
20
30
40
50
60
70
80
90
0-1 m 1-3 m 3m - 1y 1-3y 3-5y 5-12y 12-20y 21-30y 31-40y 41-50y 51-60y 61-70y
Others
H influenza
Listeria Monosytogenes
N Meningitidis
E.Faecalis
Streptococcus
S.Pneumonia
S.Aureus
Psudomonas
Acinobacter
Citrobacter
Proteus
Klebsiella
Ecoli
Fatima Khan et al. Neurology Asia 2011; 16(1) : 47 – 56

14. MRMC, Gulbarga (2008)
• February 2003 to January 2007 (2yr)
• Most of the enrolled cases were between the age group 1 month to 3 years.
• 291 cases pyogenic meningitis cases, majority of them in children <2y of age (64.9%)
Culture results of CSF specimens in
Untreated pyogenic Meningitis
patients (n=236)
Sultana Shameem et al. J. Commun. Dis. 40 (2) 2008 : 111-120

15. AMU, Aligarh (1992)
S. Fakhir, S. H. Ahmad & P. Ahmad (1992) Prognostic factors influencing mortality in meningococcal meningitis,
Annals of Tropical Paediatrics, 12:2, 149-154, DOI: 10.1080/02724936.1992.11747560
• Retrospective data of 247 cases of MM between Jan 1983 and April1990
• 58 (23.5.5 % ) cases were <5 years of age
• CFR was 16%. 28 deaths occurred within the 1st 24 hours of admission. Another 8 during the
next 24 hours, while the remaining 4 after 96 hours of hospitalization
6
52
92
97
2
8
19
11
0
20
40
60
80
100
120
1m to 1y 1-4y 5-9y 10-14y
Death
Cases

16. Recent Publications of Meningococcal Isolation In
ABM Etiology Studies Across India
Region City Center
Year of
publicatio
n
Age
Total samples
evaluated
Total bacterial
isolates
No. of
meningococ
ci
Central
Patna Patna Medical College 2013 All age 252 214 26
Jaipur NIMS 2017 1 m to 12 y 120 48 9
Udaipur RNT Medical College 2013 20 children 20 17 6
East
Bankura Bankura Sammilani Medical College 2014 2 m to 8 y 182 18
Assam Silchar Medical College & Hospital 2016 >13 y 50 35 4
North Aligarh JNMCH, Aligarh Muslim University
2011 83.8% <12 y 5859 403 10
1992 1m to 14y -- -- 247
South
Nellore Narayana Medical College & Hospital 2017 >18y 547 266 28
Gulbarga Government Hospital, MRMCH 2008 1 m to 3 y 291 199 18
Guntur Guntur Medical College 2016 1 day to 75yr 100 38 14
Bangalore MS Ramaiah Medical College & Hospital 2015 17 y - 80 y 30 17 5
Bangalore NIMHANS 2007 All age 385 284 4
Kerala GMC, Thiruvananthapuram 2015 62% children 538 52 3
Kurnool General Hospital, Kurnool 2015 1 m to 18y 74 32 3
West
Mumbai L.T.M. Medical College (Sion hospital) 2016 All age 50 15 5
Pune Sassoon General Hospital 2016 All age 50 19 2
Multicenter
Calcutta, Jaipur, Delhi, Jodhpur 1991 <12y 852 135 21
Chennai, Lucknow, Delhi, Vellore 2013 <2yr 708 89 3
References in footnotes

17. PGI Data
• 2007-2013
• Pediatrics Dept, PGIMER Chd
• A, B, C, W and non-typable
• 33 confirmed cases IMD
• 39 % under 2 years age (personal communication – data on file)

18. Indian Regulatory Updates
• Menactra (ACWY-DT) licensed for use in individuals:
• 9months through 23 months: 2 doses
• 2 years through 55 years: single dose
• Menveo (ACWY-CRM) licenced for use in individuals
• > 2 years: single dose
• MenAfriVac (A-TT) not commercially available in India
• Bivalent (AC) and Quadrivalent (ACWY) polysaccharide vaccines available
• Serogroup B vaccines not licensed in India

19. Center Investigator/s
Subjec
ts with
Data in
CRF
Subject
s
complet
ed the
study
`1
Institute of Child Health,
Kolkata
Dr. Apurba
Ghosh
51 50
2
King George's Medical
University, Lucknow
Dr. Shally
Awasthi
43 39
3
Christian Medical College,
Vellore
Dr. Rajeev
Zachariah
50 48
4
Medical College and SSG
Hospital, Baroda
Dr. Bakul
Javadekar
56 51
200 188
MTA-70: Study centers (India)
Data on file

20. 55
4.7 6.5 5.3
97.6 95.9 98.2 99.4
84.9
92.3 92.3
97
0
10
20
30
40
50
60
70
80
90
100
A C Y W-135
Percentageofsubjects Seroprotection
Data on file

21. 20.1
14.6
10.1
6 4.5
2.1
5 3.5 2.7
0
10
20
30
40
50
60
70
80
90
100
After any dose After Dose 1 After Dose 2
Tenderness Erythema Swelling
%ofsubjectsexperiencingtheendpoint
Solicited injection site reactions
*within 7 days after each and any vaccine injections
Data on file

22. 12.6
15.1 16.6
12.1
20.1
17.1
7.1 9.5
12.6
9.5
17.1
14.6
7 7.4 9.6
3.7
9.6 9
0
10
20
30
40
50
60
70
80
90
100
Fever Vomiting Crying
abnormal
Drowsiness Appetite Lost Irritability
After any dose After Dose 1 After Dose 2
Percentageofsubjectsexperiencingtheendpoint
Solicited systemic reactions
*within 7 days after each and any vaccine injections
Data on file

23. Concomitant vaccination with
routine infant/toddler vaccines

24. Trial ID
NCT#
Type
No. of Menactra
recipient
Concomitant
vaccine
NCT00422292
Safety +
Immunogenicity
2253
MMRV or PCV
NCT00384397
Safety +
Immunogenicity
1247
MMRV or PCV
NCT00483574
Safety
1374
MMRV + PCV +
HepA
NCT01359449
Safety +
Immunogenicity
61
DTaP-IPV-Hib
MTA37 MTA44 MTA48 MTA73
Concomitant vaccination of Menactra with
other routine vaccines in infants/toddlers1,2
1. Pina LM. Pediatr Infect Dis J 2012;31: 1173–1183
2. Noya et al. Can J Infect Dis Med Microbiol. 2014;25(4)

25. Menactra + PCV7: Immunogenicity
%ofchildrenwithprotectiveantibody
titers
M &
M+PCV7 1.82 5.4 2.06 6.73 1.58 2.5 4.62
MMRV+P
CV7 3.33 10.8 3.57 10.5 2.91 4.03 7.03
≥ 0.35 μg/Ml for each
90.5
97.8
95.1
81.2
100 100 100 100 100 99 100
0
20
40
60
80
100
120
A C Y W 4 6B 9V 14 18C 19F 23F
MTA37, NCT00422292

26. Menactra® Provides High Antibody Titers 3 Years
Postimmunization
BR= baby rabbit complement.
1Keyserling. Arch Pediatr Adolesc Med. 2005;159(10)
Percent of participants with SBA titers 128 against serogroups ranged from 71% to 95%

27. Vaccine Remains Effective in Adolescents up to 6
Years Postimmunization
• 69% overall effectiveness at 6 years post vaccination in adolescents 13
to 17 years of age (95% CI=50%–81%)1
Time Since
Vaccination Estimate of Vaccine Effectiveness 95% CI
<1 year 82% 54%–93%
1 to <2 years 80% 52%–92%
2 to <3 years 71% 34%–87%
3 to <6 years 59% 5%–83%
Preliminary adolescent case control data (157 cases; 180 controls—August 2012) show vaccine effectiveness
wanes over time1
1Cohn. MMWR Recomm Rep. 2013;62(RR2)

28. W Serogroup Cases by Age in Chile 2012-2015
Vaccination Program with ACYW Vaccine Started in Nov 2012,
Targeting Children 9m-5y
Vaccination program highly effective: No cases in vaccinated population
*Preliminary data until April 2015
1-4EPIDEMIOLOGIA-MINSAL . http://epi.minsal.cl/

29. At-Risk Populations
1Pollard. In: Harrison's Principles of Internal Medicine. 18th ed. 2012;chapter 143; 2Bilukha. Pediatr Infect Dis J. 2007;26(5);
3MacNeil. In: Manual for the Surveillance of Vaccine-Preventable Diseases. 5th ed. 2012; 4Liphaus. Enferm Infecc Microbiol Clin.
2013;31(2)
Impaired immune system1,2/
lack of antibodies1
Exposure through close contact with
infected person or the live bacteria
Travelers to endemic areas3
Immunocompromised2
Infants, children1,2 Caregivers3
Personnel working with
N. meningitidis2,3
Crowding1,3,4
(students, military, Hajj,
oil refineries)

30. •Addresses an unmet need in this age group
•High uptake rates likely1
•Projected 85%–87% at 9 months of age, 95% at 12–15 months of
age2
•Older infant-toddler vaccination program2
A two dose series up to 23 months
Provides the clinical benefits of a 2-4-6 month + booster schedule but with
fewer doses
Does not interfere with already congested schedules
at 2-4-6 months of age
1Apicella. In: Principles and Practice of Infectious Diseases. 7th ed, 2010; 2Pelton. Pediatr Infect Dis J. 2009;28(4)
Protecting Infants: The Rationale for Vaccinating With
Menactra® Vaccine at 9 and 12 Months of Age

31. Vaccination strategies

32. • Countries with intermediate or high (2-10 or >10 cases/ 100 000 population/year) endemic rates of IMD
or with frequent epidemics introduce appropriate large scale vaccination programmes
• Countries where disease occurs less frequently (<2 cases/ 100 000 population/year), vaccination is
recommended for defined risk groups:
o Children and young adults residing in closed communities, e.g. boarding schools or military
camps.
o Laboratory workers at risk of exposure to meningococci
o Travellers to high endemic areas
o All individuals suffering from immunodeficiency including asplenia, terminal complement
deficiencies, or advanced HIV infection
The Feb 2015 update adds to the previous recommendations specifically
concerning routine immunization of infants and young children in the African
meningitis belt with meningococcal A conjugate vaccine:
• 1-dose schedule at 9–18 months of age
• If in a specific context there is a compelling reason to vaccinate infants younger than 9
months, give 2 doses at least 8 weeks apart starting at 3 months
WHO recommendations for meningococcal vaccination
WHO position paper November 2011-11-28, http://www.who.int/immunization/documents/positionpapers/en/

33. US ACIP Recommendations
1. MMWR, March 22, 2013, Vol 62, #RR02
2. MMWR, June 20, 2014 / 63(24);527-530
• Routine vaccination of adolescents aged 11-18 years
o One dose at age 11-12 years, with a booster dose at age 16 years for persons who receive first dose before age 16 years
o MenACWY may be administered up to age 21 years as catch-up vaccination for those who have not received a dose after their 16th birthday
• Routine vaccination of persons aged ≥2 months at increased risk for meningococcal disease, including:
o anatomical or functional asplenia
o complement component deficiency.
o healthy infants in communities with a outbreak
o ≥9 months old who travel to hyperendemic or epidemic countries
• Special populations such as unvaccinated or incompletely vaccinated first-year college students living in
residence halls, military recruits, or microbiologists with occupational exposure (indication for booster dose 5
years after prior dose if at continued risk)
MenACWY-DT • 9 and 12 months
MenACWY-CRM
• 4-doses (2, 4, 6, and 12 months)
• 7-23 months: 2 doses (≥3 mon apart & after 1 yr of
age)
Booster every 5 yrs; Children who receive last dose before 7yrs age
should receive the first booster in 3 years and subsequent doses every
5 years.

34. Current IAP recommendations
• Current epidemiology does not justify routine use
• High risk recommendation
• Conjugate preferred over polysaccharide

35. IAP recommendations cont.
• Epidemics – Conjugate preferred, Monovalent vaccine maybe used
• High risk recommendation
• Immune compromised - 2 doses 8 weeks apart
• HCW, lab personnel , contacts – Single dose of MCV4, booster as appropriate
• International travel
• Study - < 21 years – 1 dose within last 5 years
• Hajj – Quadrivalent vaccine within last 3 years
• Africa – MCV4 preferred, within last 5 years.

36. Conclusions
• As of March 2015, Menactra® is approved
in 55 countries worldwide1
• Provides a robust immune response from
late infancy through adulthood against 4
out of 5 serogroups causing most of the
invasive meningococcal disease (IMD)
worldwide2
• Ten years of postlicensure safety
experience2
• No new safety concerns
• More than 70 million doses distributed
worldwide from 2005 to 20121
• WHO prequalification in March 20143
Are your
younger
patients
vaccinated?
1Sanofi Pasteur. Press release. 2005‐2012 http://www.sanofipasteur.com/en/Documents/PDF/PR-
locaux/Press%20release_Sales%20MOU%20wiht%20SK_final_April%203%202015.pdf,
2Sanofi Pasteur. Menactra® - A/C/Y/W-135 [PI]; 2014; 3WHO.
http://www.who.int/immunization_standards/vaccine_quality/pq_274_menactra_1dose_SP/en/

37. Altman DG et al. BMJ
1995;311:485