Introduction
Typhoid fever, caused by the gram-negative pathogen Salmonella
enterica serovar Typhi (S. Typhi), causes over 9 million febrile
illnesses globally each year and greater than 100,000 deaths. Recent
improvements in disease burden and mortality are at risk of being
reversed due to the escalating threat of antimicrobial resistance with
the potential for untreatable typhoid fever emerging.
Typhoid conjugate vaccines (TCVs) have shown good short-term efficacy
in phase 3 randomised clinical trials; however, there is increasing
evidence that efficacy wanes after 4 years of follow-up. Immunogenicity
data, measured by anti-Vi IgG antibody, have shown antibody decay over
time, with a more rapid decay in children who are vaccinated at less
than 1 year of age, compared with children vaccinated at older time
points. TCVs have a World Health Organisation (WHO) recommendation and
GAVI-funding for a single dose, and endemic countries have started to
introduce largely at 9-months of age, combined with the first dose of
measles-containing vaccine.
Due to the concern over waning immunogenicity and protection, the WHO
formed a working group to devise recommendations on optimising TCV
scheduling and the need for booster doses. There is, however, limited
data to inform this discussion. Data is required on the optimal time to
deliver a booster dose of vaccine that protects children through the
years where burden is often highest.
Background Data
Bangladesh
Immunogenicity Data
Data from the Bangladesh RCT demonstrated robust antibody responses
across all age groups after a single dose of TCV at 28 days but more
rapid waning in the youngest children with 5 years of follow-up.
## Site Arm Day0 Day28 Day545 Day730 Day1460 Day1825
## 1 Bangladesh <1year TCV 3.99 2928.0 23.14 18.18 13.39 10.05
## 2 Bangladesh 1-2years TCV 3.91 3068.0 62.12 44.50 27.99 24.68
## 3 Bangladesh <2years TCV 3.90 3053.0 55.90 40.70 25.58 21.94
## 4 Bangladesh <2years Control 4.30 4.3 4.70 4.60 NA NA
## 5 Bangladesh 2-4years TCV 4.80 3047.0 105.00 74.80 61.93 54.76
## 6 Bangladesh 2-4years Control 4.80 4.7 5.10 5.40 NA NA
## 7 Bangladesh >5years TCV 5.50 2899.0 199.00 161.60 158.00 93.30
## 8 Bangladesh >5years Control 5.60 5.1 6.10 6.00 NA NA
Malawi Immunogenicity
Data
The Malawi study included three distinct age groups, and followed the
same pattern with the 9-11month age group waning quicker. At 4 years
following prime, the 9-11month age category only received a booster
dose. This is the only booster study where the boost was >4years
after prime, and the only study showing a more significant rise in IgG
with booster dose compared to the original prime dose.
## Site Arm Day0 Day28 Day730 Day1460 Day1488 Day1640
## 1 Malawi 9-11months TCV 3.9 2594.0 24.0 18.8 6867 495
## 2 Malawi 9-11months Control 4.0 4.0 3.9 5.7 2912 306
## 3 Malawi 1-5years TCV 4.2 2085.0 36.9 NA NA NA
## 4 Malawi 1-5years Control 4.4 4.6 4.8 NA NA NA
## 5 Malawi 6-12years TCV 4.5 2478.0 96.3 NA NA NA
## 6 Malawi 6-12years Control 4.4 4.4 4.9 NA NA NA
Nepal Immunogenicity
Data
The Nepal trial showed the same pattern with lower peak IgG at Day 28
and faster waning in the youngest age group.
## Site Arm Day0 Day28 Day545
## 1 Nepal <5years TCV 4.45 1488.00 81.00
## 2 Nepal 5-10years TCV 4.71 2093.00 182.00
## 3 Nepal >10years TCV 10.42 2113.00 367.00
## 4 Nepal <5years Control 4.64 4.45 4.51
## 5 Nepal 5-10years Control 4.50 5.42 4.70
## 6 Nepal >10years Control 8.73 8.88 8.90
Booster Studies
In addition to the booster dose that was delivered in Malawi, these
studies have demonstrated the impact of a booster dose on immunogenicity
over time.
India Booster
Study
This study provided a booster dose at 2 years following prime in half
of the children, with the booster dose children having a higher IgG
antibody at the final timepoint.
## Site Arm Day0 Day42 Day720 Day762 Day1095 Day1825
## 1 India 6-23months TCV Boost 9.4 1902 53.8 1700 319 132.0
## 2 India 6-23months TCV No Boost 10.9 1445 57.9 NA 255 79.4
## Day2555
## 1 111.0
## 2 51.5
Nepal Booster
Study
In this Nepal study, children were vaccinated at either 9 and 15
months, or 12 and 15 months, with the children vaccinated at 9+15 months
achieving higher antibody titres, likely due to the longer gap between
doses.
## Site Arm Day0 Day28 Day90 Day118 Day180 Day208 Day545
## 1 Nepal 9 + 15 months TCV 4.27 3233 NA NA 302 2249 NA
## 2 Nepal 12 + 15 months TCV NA NA 4.3 2533 1049 1173 NA
## 3 Nepal <5years TCV 4.45 1488 NA NA NA NA 81
Indonesia Booster
Study
This confusingly designed study, have an early booster dose at 168
days, compared with a late boost at either 672 or 770 days. There was no
benefit from an early dose, and follow-up was not long enough post late
boost to determine the impact.
## Site Arm Day0 Day28 Day168 Day196 Day420
## 1 Indonesia2 6-23months TCV Early Boost 0.38 470.00 47.00 201.00 23.0
## 2 Indonesia2 6-23months TCV Late Boost 0.32 420.00 37.00 28.00 9.6
## 3 Indonesia2 6-23months TCV Late Boost 2 0.32 420.00 37.00 28.00 9.6
## 4 Indonesia2 6-23months Control 0.43 0.41 0.53 0.61 NA
## Day672 Day770 Day798
## 1 11.00 11.0 11
## 2 7.13 NA 43
## 3 7.13 5.5 351
## 4 NA NA NA
Malawi Booster
Study
The final booster study from Malawi demonstrates little benefit from
two doses at 9 and 15 months compared with a single dose at 15
months.
## Site Arm Day0 Day28 Day180 Day208
## 1 Malawi 9months TCV 4.2 2304.0 NA 292
## 2 Malawi 9 + 15 months TCV 4.1 3493.0 333.0 2572
## 3 Malawi 15months TCV 4.9 4.9 4.9 4117
Summary
These data reveal several important patterns in TCV
immunogenicity:
- Age Effects: Children who receive vaccine at 9-11
months have lower responses and more rapid waning than older vaccinated
children
- Short Prime Boost Interval: There is limited
benefit seen when the interval between prime and boost is less than two
years
- Longer Prime Boost Interval: One study from Malawi
showed a greater magnitude of antibody when boosted at 4 years following
prime, which may be a combination of time betweem dosing and age
effects
Study Concept
The INTERVAL study: Investigate the optimal interval between prime
and booster doses of TCV by randomising children, who received TCV at 9
months of age in May 2023, to receive a booster dose of TCV at one of 4
time points from 3.5 years to 5 years after their prime dose.
Primary Objective
What is the optimal timepoint for booster dose of TCV following prime
at 9 months of age, evaluated by the following outcomes:
Peak antibody response post-vaccination.
Proportion of individuals with >4-fold-rise in anti-Vi IgG
antibody 28 days post-boost at different timepoints.
Level of antibody decay prior to booster dose vaccine.
Antibody response level at study endpoint at x age of all
participants.
Overall seroincidence of infection between the different arms
over the study follow up.
Conclusions
Designing a trial that enables us to measure the response to multiple
longer intervals between prime and boost is required, to inform and
optimise TCV scheduling, balancing the antibody waning prior to booster
dosing, and antibody response after boosting to provide longer term
protection.
