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Supplementary appendix

  • December 2017
Authors:
Celina Jin
Celina Jin
Celina Jin
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Malick M Gibani at Imperial College London
Malick M Gibani
Maria Moore
Maria Moore
Maria Moore
  • This person is not on ResearchGate, or hasn't claimed this research yet.
Helene Baek Juel at University of Copenhagen
Helene Baek Juel
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Supplementary appendix
This appendix formed part of the original submission and has been peer reviewed.
We post it as supplied by the authors.
Supplement to: Jin C, Gibani MM, Moore M. Efficacy and immunogenicity of a
Vi-tetanus toxoid conjugate vaccine in the prevention of typhoid fever using a
controlled human infection model of Salmonella Typhi: a randomised controlled,
phase 2b trial. Lancet 2017; published online Sept 28. http://dx.doi.org/10.1016/
S0140-6736(17)32149-9.
!
1
!
SUPPLEMENTARY,DATA!
,
Table,S1.,–,Alternative,Clinical,Diagnostic,Criteria,(Post-hoc,analyses),
!
,
Control,
(n=31)!
Vi-TT,
(n=37)!
Vi-PS,
(n=35)!
Fever,
≥
37·5
˚
C,(any,duration),+,bacteraemia*!
18/31!(58%)!
7/37!(19%)!
9/35!(26%)!
Relative!Risk!!
!
0·33!(0·16,!0·68)!
0·44!(0·23,!0·84)!
Vaccine!Efficacy!%!!
!
67·4%!(32·3%,!84·3%)!
55·7%!(16·2%,!76·6%)!
P-value!
!
0·0009!
0·0076!
!
!
!
!
Fever,
≥
38·0
˚
C,(any,duration),+,bacteraemia*!!
16/31!(52%)!
4/37!(11!%)!
8/35!(23%)!
Relative!Risk!!
!
0·21!(0·08,!0·56)!
0·44!(0·22,!0·89)!
Vaccine!Efficacy!%!!
!
79·1%!(43·8%,!92·2%)!
55·7%!(11·0%,!78·0%)!
P-value!
!
0·0003!
0·0154!
!
!
!
!
Fever,
≥
38·0
˚
C,(any,duration),with,
subsequent,bacteraemia,
13/31!(42%)!
2/37!(5%)!
7/35!(20%)!
Relative!Risk!!
!
0·13!(0·03,!0·53)!
0·48!(0·22,!1·04)!
Vaccine!Efficacy!%!!
!
87·1%!(47·2%,!96·9%)!
52·3%!(-4·2%,!78·2%)!
P-value!
!
0·0004!
0·05!
!
!
!
!
!
*Fever!(of!a!particular!threshold)!+!bacteraemia!=!any!positive!blood!culture!and!any!fever!occurring!
in! the! same! individual! du ring! the! 14! day!challenge! period! (i.e.! no! temporal! relationship! required!
between!two!events).!!
Data! are! n/N! (%),! 95%! Confidence! Intervals! are! represented! for! relative! risk! and! vaccine! efficacy!
calculations.!
!
3
!
Table&S3.&Safety&-&Vaccine&Reactogenicity&and&Serious&Adverse&Event&Reporting&
Solicited!symptoms!(of!any!severity)!for!7!days!following!vaccination.!
&
&&
Control&&
(n=34)&
Vi-TT&
(n=41)&
Vi-PS&&
(n=37)&&
Fever!≥37·5°C!and!<38·0°C!
2!(5·9%)!
1!(2·4%)!
2!(5·4%)!
Headache!
9!(26·5%)!
14!(34·1%)!
12!(32·4%)!
Malaise!
7!(20·6%)!
9!(22%)!
4!(10·8%)!
Anorexia!
2!(5·9%)!
3!(7·3%)!
3!(8·1%)!
Myalgia!
8!(23·5%)!
13!(31·7%)!
8!(21·6%)!
Arthralgia!
5!(14·7%)!
3!(7·3%)!
4!(10·8%)!
Injection!Site!Pain!
13!(38·2%)!
25!(61%)*!
33!(89·2%)**!
Injection!Site!Erythema!
0!
1!(2·4%)!
1!(2·7%)!
Injection!Site!Induration!
0!
0!
0!
Injection!Site!Swelling!!
0!
1!(2·4%)!
0!
Serious!Adverse!Events†!
0!
1!
3!
!
Data!are!n!(%),*P=0·0499,!**P<0·0001!
†Four!Serious!Adverse!Events!were!reported!to!the!Data!Safety!and!Monitoring!Committee!during!the!
conduct!of!the!study,!however!none!were!related!to!vaccination!and!blinding!was!maintained.!One!Vi-
TT! participant! was! diagnosed! with! inflammatory! bowel! disease! and! withdrawn! from! the! study!
(symptoms! preceded!study! enrolment),!two! Vi-PS! participants! were! hospitalised!(urinary! retention!
and! semi-elective! tonsillectomy)! and! one! Vi-PS! participant! was! diagnosed! with! reactive! arthritis!
possibly!related!to!S.!Typhi!challenge!or!antibiotic!treatment.!!
!
& &
!
4
!
Table&S4.&Post-challenge&symptom&severity&scores&according&to&vaccine&group&
Control&&
Vi-TT&&
Vi-PS&&
Headache&(n)&
!
Mild!
4!
3!
2!
Moderate!
7!
5!
6!
Severe!
12!
3!
4!
Malaise&(n)&
!
Mild!
4!
1!
2!
Moderate!
11!
6!
3!
Severe!
8!
2!
6!
Anorexia&(n)&
!
Mild!
10!
6!
2!
Moderate!
6!
3!
6!
Severe!
4!
1!
0!
Abdominal&Pain&(n)&
!
Mild!
9!
8!
5!
Moderate!
6!
3!
2!
Severe!
4!
0!
2!
Nausea/Vomiting&(n)&
!
Mild!
8!
4!
4!
Moderate!
3!
0!
1!
Severe!
2!
1!
2!
Myalgia&(n)&
!
Mild!
5!
2!
4!
Moderate!
7!
5!
1!
Severe!
3!
1!
2!
Arthralgia&(n)&
!
Mild!
9!
1!
2!
Moderate!
3!
5!
3!
Severe!
4!
0!
0!
Constipation&(n)&
!
Mild!
7!
1!
7!
Moderate!
2!
3!
0!
Severe!
2!
3!
0!
Diarrhoea&(n)&
!
Mild!
5!
2!
1!
Moderate!
0!
1!
0!
Severe!
0!
0!
0!
Cough&(n)&
!
Mild!
7!
7!
2!
Moderate!
1!
0!
2!
Severe!
1!
0!
0!
&
!
!
!
!
5
!
Total&(n,&%)&–&Any&symptom&
Control&!
Vi-TT&!
Vi-PS&!
No!Symptoms!
0!(0%)!
2!(15·4%)!
0!(0%)!
Mild!
3!(12·5%)!
1!(7·7%)!
2!(15·4%)!
Moderate!
7!(29·2%)!
7!(53·8%)!
5!(38·5%)!
Severe!
14!(58·3%)!
3!(23·1%)!
6!(46·2%)!
!
!
Figure&S1.&Maximum&severity&of&typhoid&symptoms&for&diagnosed&participants&according&to&vaccine&
group.&
Solicited!symptoms!were!collected!for!21!days!following!challenge.!Severe!=!significant!interference!
with!daily!activities!requiring!codeine!analgesia,!Moderate!=! some! interference!with!daily!activities!
not!requiring!codeine!analgesia,!Mild!=!minor!interference!with!daily!activities!
!
!
& &
Control' Vi-TT Vi-PS'
0
20
40
60
80
100
%""Diagnosed"Participants
No"Symptoms
Mild
Moderate
Severe
!
6
!
Figure&S2.&–&Median&C-reactive&protein& (CRP)& level& in& typhoid&diagnosed&participants&according& to&
vaccine&group&
Median!CRP!(solid!line),!IQR!(dashed!lines),!time!point!0!represents!time!of!antibiotic!commencement.&
-14 -13 -12 -11 -10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5
0
20
40
60
80
100
Time%(days)
C-reactive%protein%(mmol/L)
Control
Vi-PS
Vi-TT
!
7
!
Figure&S3.&Logistic&regression&modelling&of&relationship&between&anti-Vi&IgG&titre&and&probability&of&
typhoid&diagnosis!!
(D0!=!day!of!challenge/day!of!typhoid!exposure).!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
&
& &
!
8
!
Supplementary&Methods&–&Inclusion&and&Exclusion&Criteria&&
Inclusion&Criteria&
Participants!must!satisfy!all!of!the!following!criteria!to!be!considered!eligible!for!the!study:!
• Agree!to!give!informed!consent!for!participation!in!the!study.!
• Aged!between!18!and!60!years!inclusive!at!time!of!vaccination.!
• In!good!health!as!determined!by!medical!history,!physical!examination!and!clinical!judgment!
of!the!study!team.!
• Agree!(in!the!study!team’s!opinion)!to!comply!with!all!study!requirements,!including!capacity!
to!adhere!to!good!personal!hygiene!and!infection!control!precautions.!
• Agree!to!allow!his!or!her!General!Practitioner!(and/or!Consultant!if!appropriate),!to!be!notified!
of!participation!in!the!study.!
• Agree! to! allow! study! staff! to!contact! his! or! her! GP! to! access! the! participant’s! vaccination!
records.!
• Agree!to!allow!Public!Health!England!to!be!informed!of!their!participation!in!the!study.!
• Agree!to!give!his!or!her!close!contacts!written!information!informing!them!of!the!participant’s!
involvement!in!the!study!and!offer!them!voluntary!screening!for!S.!Typhi!carriage.!
• Agree!to!have!24-hour!contact!with!study!staff!during!the!four!weeks!post!challenge!and!are!
able!to!ensure!that!they!are!contactable!by!mobile!phone!for!the!duration!of!the!challenge!
period!until!antibiotic!completion.!
• Agree!to! allow! the!study! team!to! hold! the!name! and! 24-hour!contact! number! of!a! close!
friend,! relative! or! housemate! who! will! be! kept! informed! of! the!study! participant’s!
whereabouts! for! the! duration! of! the! challenge! period! (from! the! time! of! challenge! until!
completion!of!antibiotic!course).!This!person! will!be!contacted!if!study! staff!are! unable! to!
contact!the!participant.!
• Have!internet!access!to!allow!completion!of!the!e-diary!and!real-time!safety!monitoring.!!
• Agree!to!avoid!antipyretic/anti-inflammatory!treatment!from!the!time!of!challenge!(Day!0)!
until!advised!by!a!study!doctor!or!until!14!days!after!challenge.!!
• Agree!to!refrain!from!donating!blood!for!the!duration!of!the!study!
• Agree! to! provide! their! National! Insurance/Passport! number! for! the! purposes! of! TOPS!
registration!and!for!payment!of!reimbursement!expenses.!
&
Exclusion&Criteria&
The!participant!will!not!be!enrolled!if!any!of!the!following!apply:!
• History! of! significant! organ/system! disease! that! could! interfere! with! trial! conduct! or!
completion.!Including,!for!example,!but!not!restricted!to:!
o Cardiovascular!disease!
o Respiratory!disease!!
o Haematological!disease!!
o Endocrine!disorders!
!
9
!
o Renal!or!bladder!disease,!including!history!of!renal!calculi!
o Biliary! tract! disease,! including! biliary! colic,! asymptomatic! gallstones! or! previous!
cholecystectomy!
o Gastro-intestinal! disease! including! requirement! for! antacids,! H2-receptor!
antagonists,!proton!pump!inhibitors!or!laxatives!
o Neurological!disease!
o Metabolic!disease!
o Autoimmune!disease!
o Psychiatric! illness! requiring! hospitalisation! or! known! or! suspected! drug! and/or!
alcohol!misuse!(alcohol!misuse!defined!as!an!intake!exceeding!42!units!per!week)!
o Infectious!disease!
• Have! any! known! or! suspected! impairment! of! immune! function,! alteration! of! immune!
function,! or! prior! immune! exposure! that! may! alter! immune! function! to!typhoid! resulting!
from,!for!example:!!
o Congenital!or!acquired!immunodeficiency,!including!IgA!deficiency!
o Human!Immunodeficiency!Virus!infection!or!symptoms/signs!suggestive!of!an!HIV-
associated!condition!
o Receipt! of! immunosuppressive! therapy! such! as! anti-cancer! chemotherapy! or!
radiation! therapy! within! the! preceding! 12! months! or! long-term! systemic!
corticosteroid!therapy!
o Receipt! of! immunoglobulin! or! any! blood! product! transfusion! within! 3! months! of!
study!start.!!
o History! of! cancer! (except! squamous! cell! or! basal! cell! carcinoma! of! the! skin! and!
cervical!carcinoma!in!situ).#
• Moderate!or!severe!depression!or!anxiety!as!classified!by!the!Hospital!Anxiety!and!Depression!
Score!at!screening!or!challenge!that!is!deemed!clinically!significant!by!the!study!doctors.#
• Weight!less!than!50kg.#
• Presence!of!implants!or!prosthesis.#
• Anyone!taking!long-term!medication!(e.g.!analgesia,!anti-inflammatories!or!antibiotics)!that!
may!affect!symptom!reporting!or!interpretation!of!the!study!results.#
• Contraindication!to!ciprofloxacin!or!macrolide!antibiotics.#
• Female!participants!who!are!pregnant,!lactating!or!who!are!unwilling!to!ensure!that!they!or!
their!partner!use!effective!contraception!30!days!prior!to!vaccination!and!continue!to!do!so!
until! two! negative! stool! samples,! a! minimum! of! 3! weeks! after! completion! of! antibiotic!
treatment,!have!been!obtained.#
• Full-time,!part-time!or!voluntary!occupations!involving:!#
o Clinical! or! social! work! with! direct! contact! with! young! children! (defined! as! those!
attending!pre-school!groups!or!nursery!or!aged!under!2!years),!or!#
o Clinical!or!social!work!with!direct!contact!with!highly!susceptible!patients!or!persons!
in! whom! typhoid!infection! would! have! particularly! serious! consequences! (unless!
willing! to! avoid! work! until! demonstrated!not! to! be! infected! with! S.! Typhi! in!
!
1
0
accordance!with!guidance!from!Public!Health!England!and!willing!to!allow!study!staff!
to!inform!their!employer).#
• Full!time,!part!time!or!voluntary!occupations!involving:#
o Commercial! food! handling! (involving! preparing! or! serving! unwrapped! foods! not!
subjected!to!further!heating)#
• Close!household!contact!with:!#
o Young!children!(defined!as!those!attending!pre-school!groups,!nursery!or!those!aged!
less!than!2!years)#
o Individual(s)!who!is!(are)!immunocompromised.!#
• Scheduled! elective! surgery! or! other! procedures! requiring! general! anaesthesia! during! the!
study!period.!
• Participants! who! have! participated! in! another! research! study! involving! an! investigational!
product!that!might!affect!risk!of!typhoid!infection!or!compromise!the!integrity!of!the!study!
within! the! 30! days!prior! to! enrolment! (e.g.! significant! volumes! of! blood! already! taken! in!
previous!study).!
• Detection!of!any!abnormal!results!from!screening!investigations!(at!the!clinical!discretion!of!
the!study!team).!
• Inability!to!comply!with!any! of!the!study!requirements!(at!the!discretion!of! the!study!staff!
and!the!participant’s!General!Practitioner).!
• Any!other!social,!psychological!or!health!issues!which,!in!the!opinion!of!the!study!staff,!may!
o Put!the!participant!or!their!contacts!at!risk!because!of!participation!in!the!study,!
o Adversely!affect!the!interpretation!of!the!primary!endpoint!data,!
o Impair!the!participant’s!ability!to!participate!in!the!study.!
• Having!previously!received!any!typhoid!vaccine!!
• Having!been!resident!in!an!enteric!fever!endemic!country!for!6!months!or!more.!
• Have!previously!been!diagnosed!with!laboratory-confirmed!typhoid!or!paratyphoid!infection!
or!been!given!a!diagnosis!compatible!with!enteric!fever.!
• Have!participated!in! previous!typhoid!or!paratyphoid!challenge!studies!(with! ingestion! of!
challenge!agent).!
• Have! received! vaccination! with! a! vaccine! containing! tetanus! toxoid! within! the! past! 12!
months.!!
• Have!any!history!of!allergy!to!vaccine!components!(including!tetanus!toxoid!and!diphtheria!
CRM!protein).!!
• Have!a!prolonged!corrected!QT!interval!(>450!milliseconds)!on!ECG!screening.!!
&
!
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Linked Research

Efficacy and immunogenicity of a Vi-tetanus toxoid conjugate vaccine in the prevention of typhoid fever using a controlled human infection model of Salmonella Typhi: a randomised controlled, phase 2b trial
Article
September 2017
Celina Jin · Malick M Gibani · Maria Moore · Helene Baek Juel · Andrew J Pollard