An anti-tetanus vaccine

Ray Borrow

ray.borrow@phe.gov.uk

Neonatal tetanus

2

§  Maternal and neonatal tetanus is still a substantial but preventable cause of mortality in many developing countries.

§  Case fatality from these diseases remains high and treatment is limited by scarcity of resources and effective drug treatments.

§  The Maternal and Neonatal Tetanus Elimination Initiative, launched by WHO and its partners, has made substantial progress in eliminating maternal and neonatal tetanus.

§  Sustained emphasis on improvement of vaccination coverage, birth hygiene, and surveillance, with specific approaches in high-risk areas, has meant that the incidence of the disease continues to fall.

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By August 2015, 21 countries have still not reached the MNT elimination status.

http://www.who.int/immunization/diseases/MNTE_initiative/en/

Global maternal and neonatal tetanus elimination

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MenAfriVac

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MenAfriVac developed by the Serum Institute of India, Ltd. MenAfriVac contains 10–33 µg of TT per dose or 3–9 Lf (limit of flocculation).

6

Using TT as a carrier protein became an attractive option for 4 reasons: 1.  Conjugate vaccines using TT as a carrier protein had been

successfully developed.

2.  Both neonatal and non-neonatal tetanus were public health problems in sub-Saharan Africa.

3.  Conjugate vaccines that were made with TT had shown an anti-tetanus serological response when tested.

4.  Meningococcal conjugate vaccines using TT as a carrier protein enhance immune response to coadministered TT conjugated vaccines such as Hib.

Tetanus toxoid as a carrier protein

Anti-TT IgG response following meningococcal CRM197 or TT conjugate vaccination

7 Burrage M et al. Infect Immun 2002;70:4946-54.

0.01

0.1

1

10

100

MCC-CRM MCC-CRM MCC-TT MCC-CRM MCC-CRM MCC-TT

anti-

TT G

MC

s IU

/mL

Pre-school (3.5 to 6 years)

School leavers (13 to 18 years)

MCC-CRM = Meningitec or Menjugate MCC-TT = NeisVac-C

8

0

2

4

6

8

10

12

MCC-CRM MCC-TT MCC-CRM MCC-TT

anti-

PRP

IgG

GM

C µ

g/m

L

Co-administration of meningococcal serogroup C conjugated to TT with DTaP/IPV/Hib-TT or DTwP/Hb-TT enhances Hib

IgG responses

DTaP/IPV/Hib-TT DTwP/Hib-TT

Kitchin N et al. Vaccine 2006;24:3964-70.

What have we learnt with regards to tetanus serology from the clinical trials of PsA-TT

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§  PsA-TT-001. Phase I in India. Healthy adults aged 18–35 years.

§  PsA-TT- 002. Healthy toddlers aged 12–23 months.

§  PsA-TT-003 and 3a. Healthy Africans aged 2–10, 11–17, and 18–29 years and Indians aged 2–10 years.

10

0

5

10

15

20

25

30

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

anti-

TT Ig

G G

MC

(95%

CI)

IU/m

L

Baseline4weeks24weeks48weekspostvaccina3onpostvaccina3onpostvaccina3on

PSA-TTACWYTT

Borrow R et al. Clin Infect Dis 2015;61 (Suppl 5):S570-7.

PsA-TT-001. Anti–tetanus toxoid IgG GMCs for healthy adults aged 18–35 years following

either PSA-TT, meningococcal ACWY polysaccharide vaccine, or TT vaccine.

PsA-TT-002. Anti–TT IgG GMCs for healthy toddlers aged 12–23 months following PsA-TT vaccine

11

0.1

0.2

0.4

0.8

1.6

3.2

6.4

12.8

25.6

51.2

1 2 3 4 5 6

ant

i-TT

IgG

GM

C (9

5% C

I) IU

/mL

Visit 1 Visit 3 Visit 4 Visit 7 Visit 7 Visit 7 Baseline 4 weeks 10 months 4 weeks 4 weeks 4 weeks

post PSA-TT post PSA-TT. post post post revaccination. revaccination revaccination with PSA-TT with ACWY with Hib-TT

Borrow R et al. Clin Infect Dis 2015;61 (Suppl 5):S570-7.

Sites: Mali & the Gambia

12

0.05

0.1

0.2

0.4

0.8

1.6

3.2

6.4

12.8

25.6

51.2

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

anti-

TT Ig

G G

MC

(95%

CI)

IU/m

L

African Indian African African 2 to 10 years 2 to 10 years 11 to 17 years 18 to 29 years

pre-vaccination 4 weeks post PSA-TT 4 weeks post ACWY

African sites: Mali, Senegal, and the Gambia

PsA-TT-003 and PsA-TT-003a. Anti–TT IgG GMCs for healthy Africans aged 2–10, 11–17, and 18–29 years and Indians aged 2–10 years following vaccination

with either PsA-TT vaccine or meningococcal ACWY polysaccharide vaccine.

Borrow R et al. Clin Infect Dis 2015;61 (Suppl 5):S570-7.

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Surveillance Data for Neonatal Tetanus

Surveillance data for neonatal tetanus cases in meningitis belt countries was obtained from the WHO website. Data were prepared listing NT cases and maternal TT2+ coverage from 2009 to 2013 for 3 categories of meningitis belt countries: Ø  Countries that had completed countrywide PsA-TT vaccination

campaigns in 1- to 29-year-olds by 2012

Ø  Countries with either partial coverage with PsA-TT or with campaigns still proceeding.

Ø  Countries that had not yet begun PsA-TT campaigns.

http://apps.who.int/immunization_monitoring/globalsummary/timeseries/tsincidencentetanus.html

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Annual Reported Cases of Neonatal Tetanus and TT2 Coverage From 2009 to 2013 for Countries

Completing Countrywide PsA-TT Campaigns in Persons Aged 1–29 Years 2009 2010 2011 2012 2013

Country Year of PsA-TT

campaign

NT cases

% TT2 coverage

NT cases

% TT2 coverage

NT cases

% TT2 coverage

NT cases

% TT2 coverage

NT cases

% TT2 coverage

Burkina Faso

2010 6 85 2 85 2 88 1 88 0 88

Mali 2010/11 13 92 7 85 11 89 10 89 12 85

Niger 2010/11 14 84 13 84 11 84 3 84 1 81

Gambia 2011 0 91 0 91 2 91 0 92 0 82

Chad 2012 146 60 279 60 215 60 225 43 176 50

Senegal 2012 16 88 12 88 21 88 14 91 4 91

Total 195 313 260 253 193

Cases of neonatal tetanus in 2013 declined in 5 of the 6 countries, with Mali being the sole exception.

Borrow R et al. Clin Infect Dis 2015;61 (Suppl 5):S570-7.

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Average annual cases of neonatal tetanus and TT2 coverage in Meningitis Belt countries that

have introduced or have yet to introduce PsA-TT Average Annual Cases of NT % TT2 Coverage

Campaign area 2009–2011 2012–2013 % Change 2009–2011 2012–2013 % Change

No PsA-TT campaigns†

121.9 139.5 +14.4% 85.6 79.2 −7.4%

Before campaign

After campaign

% change Before campaign

After campaign

% change

Campaigns in part of country‡

64 68 +6.5% 86.6 85.8 −0.9%

Campaigns covering all

country*

260.2 194.5 −25.4% 82.2 81.0 −2.5%

† Côte d’Ivoire, Ethiopia, Mauritania, Democratic Republic of Congo, Guinea, Central African Republic. ‡ Cameroon, Togo, Benin, Ghana * Burkina Faso, Mali, Niger, Gambia, Chad, Senegal

Borrow R et al. Clin Infect Dis 2015;61 (Suppl 5):S570-7.

When the average annual cases of neonatal tetanus in the 5 countries were compared before and after the PsA-TT campaigns, there was a 25% reduction in NT cases. Maternal TT2 coverage was unchanged.

Seroprevalence studies in sub-Saharan Africa

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Ø  Immunity to tetanus among high school adolescents girls - Ibadan, Nigeria - June to August 2012 - pre-MenAfriVac campaign - Used Tetanos Quick Stick (a immunochromatographic test) - ≥ 0.1 IU/mL

Ø  Immunity to tetanus by age and sex in 1 to 29 year olds - Bamako, Mali - pre and post MenAfriVac campaign - used standardised bead based immunoassay - quantified assay

Immunity against tetanus among high school adolescents girls in Ibadan, Nigeria

17 Orimadegun et al. Italian Journal of Pediatrics 2014, 40:29

Trend of age-specific seroprevalence of protective immunity against tetanus

38.1% positive overall Private school 55.3% Significantly higher than public school 34.6%. No significant association between socio-economic class and level of tetanus Immunity.

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0.2

.4.6

.81

Males Females Males Females

1-2yrs

3-5yrs

6-10yr

s

11-17

yrs

18-29

yrs1-2

yrs3-5

yrs

6-10yr

s

11-17

yrs

18-29

yrs1-2

yrs3-5

yrs

6-10yr

s

11-17

yrs

18-29

yrs1-2

yrs3-5

yrs

6-10yr

s

11-17

yrs

18-29

yrs

Pre-MenAfriVac 2010 Post-MenAfriVac 2012

0 to <0.1 0.1 to <1.0 1.0 to <10.0 >=10.0

Prop

ortio

n wi

th Te

tanu

s Tox

oid Ig

G (IU

/mL)

Anti-TT IgG levels (IU/mL) by sex and age before and after a PsA-TT mass-vaccination

campaign in Mali

Basta NE et al. Clin Infect Dis 2015; 61(S5):S578–85.

All age groups evidenced statistically significant changes in the percentage with TT IgG levels ≥0.1 IU/mL 2 years after PsA-TT introduction. Despite these increases, 2 years after PsA-TT introduction, 11.6% of participants still had TT IgG <0.1 IU/mL.

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§  NT surveillance data from meningitis belt countries are interesting but incomplete.

§  In countries that have mounted national campaigns, there has been a decrease in reported cases of NT by 25%.

§  This has not been noted in countries that have not yet mounted campaigns or in countries that had partial campaigns.

§  NT is an underreported disease, and caution needs to be taken in over interpreting surveillance data.

§  Nonetheless, the information from countries that have completed PsA-TT campaigns is encouraging and is consistent with the tetanus serological data from the PsA-TT clinical trials in Africa.

§ Increasing immunity to tetanus in women of reproductive age doubtlessly happened at a result of the introduction of PsA-TT, but the extent to which this has translated to decreases in NT needs to be further quantified.

Conclusions

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Acknowledgements

F Marc La Force Yuxiao Tang Nicole Basta Samba O. Sow Prasad Kulkarni Caroline Trotter Brian Greenwood Ahmadu Yakubu Olivier Manigart Abdoulaye Berthe Uma Onwucheckwa Awa Traore Maria Nascimento Rachael Almond Sima Patel Sarah Frankland