N. meningitidis;From Global to Local Perspectives

Professor Fahad Al-Zamil Professor and Consultant Pediatric Infectious Diseases,

Head of Infectious Disease Unit

King Saud University

Edward Jenner

Edward Anthony Jenner (17 May 1749 – 26 January 1823) was an English scientist who studied his natural surroundings in Berkeley, Gloucestershire. Jenner is widely credited as the pioneer of smallpox vaccine,[1] and is sometimes referred to as the "Father of Immunology"; his works have been said to have "saved more lives than the work of any other man".[2][3][4]

3

James Phipps

James Phipps (1788-1853), as an eight year old boy, and the son of Edward Jenner's gardener, was the first person given the cowpox vaccine by Edward Jenner. Phipps was often used as an living proof that Jenner's vaccine worked.

Phipps was exposed to the smallpox virus multiple times over the next twenty years, but successfully resisted infection, proving the efficacy of Jenner's vaccination. Edward Jenner Vaccinating 8 year old James

Phipps on 14 May 1796

4

Louis Pasteur27 December, 1822 – 28 September, 1895

The great revolution in the vaccination science occurred thanks to the genius French chemist and microbiologist Louis Pasteur who developed an attenuated vaccines to prevent cholera, anthrax and rabies.

Louis Pasteur was the first person to use the terms Vaccine and attenuated.

His body lies beneath the Institute Pasteur in France

Joseph Meister (21 February 1876 - 16 June 1940) was the first person to be inoculated against rabies by Louis Pasteur, and the first person to be successfully treated for the infection.

In 1885, nine-year-old Meister was bitten by a rabid dog after provoking it by poking it with a stick. Pasteur decided to treat the boy with a rabies virus grown in rabbits and weakened by drying, a treatment he had earlier tried on dogs. The treatment was successful and the boy did not develop rabies.

Joseph Meister

Article from the French newspaper “Le Petit Journal” regarding Joseph Meister’s reported suicide during the German occupation of Paris during World War 1. During the German occupation of Paris,

Meister committed suicide by shooting himself with his World War I service revolver rather than allow German soldiers enter Pasteur’s crypt(secret burial place or tomb).

Meningococcal Disease

Global epidemiology

Local epidemiology

Shortcomings of Meningococcal polysaccharide vaccines

Conclusion

8

Four-month-old female with gangrene of hands and lower extremities due to meningococcemia

9

Four-month-old female with gangrene of feet due to meningococcemia

10

Four-month-old female with gangrene of hands due to meningococcemia

11

Four-month-old female with gangrene of hand due to meningococcemia

12

Neisseria meningitidis; The pathogen

Strictly human pathogen

Transmission by aerosol droplet, crowding facilitates

Asymptomatic carriage in 10-30%

Under 1% of carriers become symptomatic

Invasive diseases include: meningitis, meningococcemia, pneumonia, septic arthritis

High capacity DNA transformation and recombination systems allow acquisition of genes by horizontal gene transfer

13

Difficult to Diagnose, Rapidly Lethal1

Reference: 1. Thompson MJ, et al. Lancet. 2006;367(9508):397-403.

12–15 hoursCharacteristic

15–~24 hoursLate

4–8 hoursNonspecific

Typical time course of meningococcemia and meningitis

Fever, irritability, nausea or vomiting,

drowsiness, poor appetite, sore throat, coryza, general aches

Hemorrhagic rash, neck pain,

meningismus,photophobia

Confusion or delirium, seizure, unconsciousness;

possible death

Hospital admission at median of ~19 hours

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Meningitis Fever and

headache (flu-like symptoms)

Stiff neck Altered mental

status Seizures

3%–10% fatality rate

Meningococcemia Rash Vascular damage Disseminated

intravascular coagulation

Tissue damage Shock Death within 24 hours

20%–40% fatality rate

Clinical Presentation

Apicella MA. In: Principles and Practice of Infectious Diseases. 1995:1896-1909; Jodar L, et al. Lancet. 2002;359:1499;Granoff DM, et al. In: Plotkin SA, ed. Vaccines. 4th ed. Philadelphia: W.B. Saunders Co; 2004;Rosenstein NE, et al. N Engl J. 2001;344:1378

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Serious Outcomes of Meningococcal Disease

Death (10%15%) Long-term sequelae (10%15%)– Deafness– Cranial nerve palsy– Retardation– Limb loss

Granoff DM, et al. In: Plotkin SA, ed. Vaccines. 4th ed. Philadelphia: W.B. Saunders Co; 2004

Meningococcal Disease

Global epidemiology

Local epidemiology

Shortcomings of Meningococcal polysaccharide vaccines

Conclusion

17

Adapted from Granoff DM, Feavers IM, Borrow R. Meningococcal vaccines. In: Plotkin SA, Orenstein WA, editors. Vaccines. 4th ed. Philadelphia: Saunders; 2004: 959-87

N. meningitidis Serogroup Characteristics

A

Leading cause of disease worldwide due to large African epidemicsMajor cause of endemic disease in Africa, China, Russia, IndiaRare in Americas, Western Europe

BMajor cause of endemic disease in Europe, the Americas, Southeast Asia, Oceana

C Major cause of endemic disease in Europe, the Americas, Oceania

YSmall percentage of infections worldwideIncreasing problem in North America among adolescents

W-135

Small percentage of infections worldwideRecent worldwide outbreaks related to Hajj pilgrimagePotential agent for large-scale epidemics (Africa)

X, 29E, Z, … Very rare cause of infections worldwide

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* Provisional data(N is total serogrouped strains. Other includes other serogroups and non groupable strains)

AFRICAN MENINGITIS BELT

2003-2004(n=501)

Other1,2%

A79%

W-13520%

AUSTRALIA 2004(n=335)

C21%

A0,3%

B73%

W-1353,6%

Y2,4%

WESTERN EUROPE 2002

(n=3,982)

A0,1%

C29%

Other1,0%

B64%

W-1353,6%

Y2,3%

RUSSIA 2002-2004(n=1,899)

B32%

A36%

C22%

Other10%

CHILE 2003(n=193)

Other5%

C14%

B78%

W-1351%

Y2%

UNITED STATES 2003(n=200)

Y27%

C21%

B44%

Other6%W-135

2%

TAIWAN 2001(n=43)

Y19%

A4,7%

W-13541%

B33%

C2,3%

THAILAND 2001(n=36)

Other2%

B81%

W-13517%

SAUDI ARABIA 2002

(n=21)

B10%

W-13576%

A14%

BRAZIL 2003Sao Paulo state

(n=426)

B39%

C57%

Other4%

COLOMBIA 2004(n=37)

Y32%

B51%

W-1353%C

14%

NEW ZEALAND 2004(n=252)

C8%

Other0,8%

B87%

W-1353,6%

Y0,4%

SOUTH AFRICA 2005(n=414)

Other0,5%C

5%

B14%

W-13562%

A6%

Y13%

URUGUAY 2001(n=53)

C11%

B83%

Other6%

Canada 2003*(n=148)

Y25%

C24%

B43%

Other1%W-135

7%

AFRICAN MENINGITIS BELT

2003-2004(n=501)

Other1,2%

A79%

W-13520%

AUSTRALIA 2004(n=335)

C21%

A0,3%

B73%

W-1353,6%

Y2,4%

WESTERN EUROPE 2002

(n=3,982)

A0,1%

C29%

Other1,0%

B64%

W-1353,6%

Y2,3%

RUSSIA 2002-2004(n=1,899)

B32%

A36%

C22%

Other10%

CHILE 2003(n=193)

Other5%

C14%

B78%

W-1351%

Y2%

UNITED STATES 2003(n=200)

Y27%

C21%

B44%

Other6%W-135

2%

TAIWAN 2001(n=43)

Y19%

A4,7%

W-13541%

B33%

C2,3%

THAILAND 2001(n=36)

Other2%

B81%

W-13517%

SAUDI ARABIA 2002

(n=21)

B10%

W-13576%

A14%

BRAZIL 2003Sao Paulo state

(n=426)

B39%

C57%

Other4%

COLOMBIA 2004(n=37)

Y32%

B51%

W-1353%C

14%

NEW ZEALAND 2004(n=252)

C8%

Other0,8%

B87%

W-1353,6%

Y0,4%

SOUTH AFRICA 2005(n=414)

Other0,5%C

5%

B14%

W-13562%

A6%

Y13%

URUGUAY 2001(n=53)

C11%

B83%

Other6%

Canada 2003*(n=148)

Y25%

C24%

B43%

Other1%W-135

7%

Global Serogroup Distribution in the early 2000’s

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General Epidemiological Pattern of Invasive Meningococcal Disease

Different populations have widely varying incidence rates of invasive meningococcal infection

African Meningitis Belt countries100 to 800 cases/100,000/yr

Hajj pilgrims25/100,000/yr

Freshmen in dormitories5 to 13/100,000/yr

Military recruits2 to 5/100,000/yr

Industrialized countries

1-3/100,000/yr

(3)

(1-2)

(4-6)

(7-8)

(9-11)

[1] World Health Organization. Control of Epidemic Meningococcal Disease. WHO Practical Guidelines. WHO/EMC/BAC/98.3. 2nd ed. Geneva, Switzerland, World Health Organization, 1998. Available at: http://www.who.int/emc-documents/meningitis/whoemcbac983c.html. Accessed April 12, 2005. [2] WHO. Wkly Epidemiol Rec 2003;78:294-6; [3] Wilder-Smith A, et al. Clin Infect Dis 2003;36:679-83; [4] Harrison LH, et al. JAMA 2001;286:694-9; [5] CDC. MMWR Recomm Rep 2000;49(RR-7):11-20; [6] Neal KR, et al. Epidemiol Infect 1999;122:351-7; [7] Brundage, JF, et al. Clin Infect Dis 2002;35:1376-81; [8] Spiegel A, et al. Santé 1996;6:383-8; [9] CDC. MMWR Morbid Mortal Wkly Rep 2004;51(53):1-84; [10] Squires SG, et al. Can Commun Dis Rep 2004; 30:17-28; [11] European Union Invasive Bacterial Infection Surveillance network. Invasive Neisseria meningitidis in Europe 2002. Dec 2003. Available at http://www.euibis.org/documents/2002_meningo.pdf. Accessed April 12, 2005.

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Hajj and Umra Visitors

E.Asia & Pacific169,437 visitors

Africa369,727 visitors

Americas7,576 visitors

Europe168,946 visitors

Middle East3,449,212 visitors

South Asia1,755,992 visitors

Map courtesy of BYU Geography Department, Data from Kingdom of Saudi Arabian Department of Tourism

2007

Meningococcal Disease

Global epidemiology

Local epidemiology

Shortcomings of Meningococcal polysaccharide vaccines

Conclusion

22

Reported Cases of Meningococcal DiseaseSaudi Arabia, 1970 – 2008

1970

1975

1980

1985

1990

1995

2000

2005

0

500

1000

1500

2000

2500

3000

year

nu

mb

er o

f re

po

rted

cas

es

Source: Kingdom of Saudi Arabia, Ministry of Health, February 2009

23

Reported Cases of Meningococcal DiseaseSaudi Arabia, 1994 – 2008

1995 1998 2001 2004 20070

50

100

150

200

250

300

350

400

year

nu

mb

er o

f re

po

rted

cas

es

Source: Kingdom of Saudi Arabia, Ministry of Health, February 2009

24

Meningococcal Cases by Region,Saudi Arabia, 1999 - 2003

1999 2000 2001 2002 20030

50

100

150

200

250

300

350

Others

Riyadh

Jeddah

Madinah

Makkah

year

nu

mb

er o

f re

po

rted

cas

es

Source: Kingdom of Saudi Arabia, Ministry of Health, February 2009

25

Meningococcal Cases by Age Group,Saudi Arabia, 1999 - 2003

1999 2000 2001 2002 20030

50

100

150

200

250

300

350

45 +

15 - 44 yrs

5 - 14 yrs

1 - 4 yrs

< 1yr

year

nu

mb

er o

f re

po

rted

cas

es

Source: Kingdom of Saudi Arabia, Ministry of Health, February 2009

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Meningococcal Disease by Serogroup*Saudi Arabia, 1994 – 2008

1994-1998 1999-2003 2004-20080

50

100

150

200

250A B C W-135 Y other

5-year period

nu

mb

er p

f re

po

rted

cas

es

Source: Kingdom of Saudi Arabia, Ministry of Health, February 2009

* Cases for whom a serogroupwas identified and reported

Meningococcal Disease

Global epidemiology

Local epidemiology

Shortcomings of Meningococcal polysaccharide vaccines

Conclusion

28

Shortcomings of current of polysaccharide Vaccine

T-cell-independent immune response producing no memory Absence of herd immunity in unvaccinated population No effect on carriage status Frequent revaccination needed each 3 years. Hypo-responsiveness occurred upon revaccination. No Boosting effect. Poor immunogenicity among the younger age groups.

Dose those shortcomings of local impact?

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Demonstrated hyporesponsiveness upon MPSV repeated vaccination

MPSV naïve Vaccinated once Vaccinated > once0

100

200

300

400

500

600

700

800

Prior to vaccination 1M post vaccination

Serogroup C rSBA titers pre and 1month post MPSV vaccination

rSBA GMTs

Jokhdar H, Borrow R, Sultan A et al. Immunologic Hyporesponsiveness to Serogroup C but Not Serogroup A following Repeated Meningococcal A/C Polysaccharide Vaccination in Saudi Arabia. Clin Diagn Lab Immunol. 2004;11:83-88

30

AlMazrou Y, Khalil M, Borrow R, et al. Serologic responses to ACYW135 polysaccharide meningococcal vaccine in Saudi children under 5 years of age. Infection and Immunity 2005;73:2932-39.

31

In Saudi Arabia, very young children demonstrated relatively poor immune response to Meningococcal Polysaccharide Vaccine

AL-Mazrou Y, Khalil M, Borrow R et al. Serologic Responses to ACYW135 Polysaccharide Meningococcal Vaccine in Saudi Children under 5 Years of Age. Infect Immun. 2005;73:2932-39

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Conclusion

Meningococcal disease is sever and devastating.

Saudi Arabia is at high risk due to several factors

The currently used MPSV4 having several limitations.

The solution is to shift to the modern MCV4

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Expanded Program of Immunization

in Saudi Arabia - 2009

Meshkhas AA. Guidelines to Expanded Program of Immunization staff (Arabic title). Riyadh: Saudi Ministry of Health; 2006.

AGE EPI 1991 EPI 2002 EPI 2009

At birth BCG HepB1 BCG HepB1 BCG HepB1

6 weeks DTwP1 HepB2 OPV1    

2 months   DTwP-Hib1 HepB2 OPV1 DTwP-Hib1-HepB2 IPV1 PCV71

3 months DTwP2 OPV2    

4 months   DTwP-Hib2 OPV2 DTwP-Hib2-HepB3 OPV1 PCV72

5 months DTwP3 OPV3    

6 months Measles HepB3 DTwP-Hib3 HepB3 OPV3 DTwP-Hib3-HepB4 OPV2 PCV73

9 months     Measles + MCV4

12 months MMR MMR1 MCV4 MMR1 OPV3 Varicella1 PCV74

18 months DTwP4 OPV4 DTwP-Hib4 OPV4 DTwP-Hib4 OPV4 HepA1

24 months DTwP5 OPV5 MMR2 DTwP5 OPV5 HepA2

4-6 years     MMR2 Varicella2 DTwP5 OPV5