A major event for new TB vaccines

Article (PDF Available)inThe Lancet 381(9871) · February 2013with14 Reads
DOI: 10.1016/S0140-6736(13)60137-3 · Source: PubMed
www.thelancet.com Vol 381 March 23, 2013
One of the great quests of contemporary medical research
is the search for an improved tuberculosis vaccine—one
that provides greater and more consistent protection
against tuberculosis than the BCG vaccine can achieve.
The stakes are high. The venture is costly and risky, but
has a huge potential payoff . A high-effi cacy vaccine
could revolutionise control of tuberculosis, shifting the
emphasis from treatment to prevention. As the case
numbers slowly fall in high-burden countries, and as new
strains of drug-resistant tuberculosis emerge, a novel
and transformational technology for tuberculosis control
would be cause for great celebration.
US$70–100 million is spent on vaccine research for
tuberculosis every year and the pipeline of candidate
vaccines is now longer and wider than ever before.
each of the candidates moves from preclinical to clinical
stages, passing tests for safety and immunogenicity,
experi ments to assess effi cacy in human beings are
major events.
Against this background, Michele Tameris and col-
leagues report in The Lancet results of a phase 2b trial in
infants in South Africa of the vaccine modifi ed Vaccinia
virus Ankara expressing antigen 85A (MVA85A).
Although the primary objective of the trial was to
assess safety, it also made a preliminary assessment of
effi cacy—and many readers will go, with halted breath,
straight to the conclusions about effi cacy. They will
be confronted with results that are, on the face of it,
disappointing, show ing little evidence of effi cacy in
terms of prevention of tuberculosis or infection with
Mycobacterium tuberculosis.
Although the trial raised no concerns about safety,
the absence of any detectable effi cacy presents the
tuberculosis vaccine community with a serious
challenge. However, the fi ndings reported by Tameris
and colleagues are not a terminal prognosis for
MVA85A, or for any of the other tuberculosis vaccines
in develop ment. To understand why, the results of this
particular trial need to be put in a wider context.
Two main strategies exist for development of
tuberculosis vaccines.
The rst is to replace the widely
used BCG vaccine with an improved whole-organism
vaccine, which is either a recombinant BCG or an
attenuated strain of M tuberculosis. The second is to
develop a subunit boosting vaccine, which is designed
to enhance whatever protection is already provided by
BCG. MVA85A is an example of the latter strategy.
In their elegant randomised, placebo-controlled
trial, Tameris and colleagues followed up 2794 BCG-
vaccinated infants for up to 37 months (median 24·6,
IQR 19·2–28·1) in two nearly equal groups. 39 (2·8%)
of 1395 infants in the placebo group (Candida skin
test antigen) satisfi ed the primary defi nition of active
tuberculosis, of whom 20 were microbiologically
confi rmed. 32 (2·3%) of 1399 infants in the vaccine
group (MVA85A) satisfi ed the primary defi nition of
active tuberculosis, of whom 22 were microbiologically
confi rmed. Thus, vaccine effi cacy was 17·3%, which was
not distinguishable from zero (95% CI –31·9 to 48·2).
Neither was there any evidence for protection against
M tuberculosis infection, as determined by an in-vitro
interferon γ release assay (QuantiFERON-TB Gold In-
tube; Cellestis, Australia). During the trial, 349 (13%)
of 2792 participants became positive on this assay,
171 (12%) in the placebo group and 178 (13%) in the
vaccine group. The ratio of apparent infection to disease
was thus about ve to one considering all cases of
tuberculosis, or eight to one for confi rmed cases only.
A major event for new tuberculosis vaccines
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Published Online
February 4, 2013
See Articles page 1021
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Mycobacterium tuberculosis
www.thelancet.com Vol 381 March 23, 2013
These results might provide little optimism that
MVA85A will deliver a new tuberculosis vaccine. But
this trial was designed to answer only one of a series of
important questions about new tuberculosis vaccines.
Before drawing any rm conclusions, we need to answer
several other questions.
First, could MVA85A be eff ective against infant and
child hood tuberculosis when used independently of BCG?
Substantial evidence shows that BCG protects young
children against tuberculosis; so to seek yet more pro-
tection might be asking too much of MVA85A. This poses
a major problem for tuberculosis vaccine research because
BCG is recommended for infants in all countries with high
burdens of tuberculosis. One of the explanations for the
BCG vaccine’s poor performance in some populations is
that exposure to other mycobacterial antigens can mask
its eff ect—perhaps BCG masked the eff ect of MVA85A?
Second, in view of the variable performance of BCG
in diff erent populations, can we assume that the same
results will be obtained with MVA85A in other popu-
lations? South Africa has been favoured for vaccine trials
because the transmission rate of M tuberculosis and burden
of disease are comparatively high. The question remains
whether the characteristics that are responsible for this
high burden somehow militate against immunisation.
Third, could MVA85A, working as a booster to BCG,
protect adolescents and adults against pulmonary
tuberculosis in a way that it cannot protect infants?
Immunologically naive infants and young children do
not develop pulmonary tuberculosis in the same clinical
form as adults, and adult pulmonary tuberculosis is the
main target of tuberculosis control.
Fourth, might this vaccine work if administered
to people infected with HIV? MVA85A is also being
tested in HIV-positive adults in Senegal and South
Africa. If these trials are successful, MVA85A might
be a replacement for BCG which, as a live-attenuated
vaccine, is not recommended for people living with HIV.
Fifth, could MVA85A be effi cacious against severe
forms of tuberculosis, including pulmonary tuberculosis,
without preventing infection or mild forms of disease?
A high effi cacy against severe disease could have been
masked in this trial which, by use of invasive diagnostic
methods including gastric lavage, detected relatively
mild forms of tuberculosis infection or disease.
Sixth, how does the effi cacy of MVA85A compare
with other vaccine candidates now in phase 2b trials?
The world eagerly awaits the next set of results on the
effi cacy of two other subunit boosting vaccines, both
from trials in South Africa: AERAS-402/Crucell Ad35 in
infants and GlaxoSmithKline’s GSK M72 in adults.
Finally, key questions remain about immunogenicity.
The word itself might be misleading, insofar as it is
used to describe any measurable immunological eff ect,
irrespective of the implications for protection. MVA85A
is described as modestly immunogenic because it
generated moderate antigen-specifi c Th1 and Th17
responses (compared with other populations) although
it showed no evidence of protection against infection or
disease. A large bank of samples collected in the recent
trial have yet to be examined and analysed—and might
yet help to identify immunological factors that are
characteristic of individuals who do and do not develop
tuberculosis. The identifi cation of a valid measure of
protective immunity against tuberculosis would be a
discovery of overwhelming importance.
Apart from the spur to solve all these problems,
the search for a new tuberculosis vaccine has other
sources of inspiration. It remains an astonishing fact
that children aged 5–10 years are very resistant to
development of active tuberculosis.
Is this resistance
suggestive of an immunological mechanism that could
be exploited for vaccine development? In preclinical
research, investigations with animals continue to
generate new and promising results. One example is
H56, a vaccine that combines antigens characteristic of
early infection and latency, and seems to protect mice
against tuberculosis disease before and after exposure to
A vaccine that could protect everyone before
and after infection is an epidemiologist’s dream.
Now is a key moment in tuberculosis vaccine research.
Trials such as that of Tameris and colleagues are at last
generating hard evidence about protection against
tuberculosis in human beings, the most important goal
of immunisation. If the history of tuberculosis vaccine
research teaches us anything, it is to expect surprises. We
need to go on playing the high-stakes game.
*Christopher Dye, Paul E M Fine
HIV/AIDS, Tuberculosis, Malaria and Neglected Tropical Diseases,
World Health Organization, Geneva, Switzerland (CD); and
Department of Infectious Disease Epidemiology, London School
of Hygiene and Tropical Medicine, London, UK (PEMF)
www.thelancet.com Vol 381 March 23, 2013
Folic acid fortifi cation, instituted in the mid to late
1990s in the USA and Canada, and now in more than
50 countries,
has been highly eff ective for its intended
purpose—to reduce the incidence of neural tube defects
(eg, spina bifi da and anencephaly).
However, lingering
concerns about the safety of excess intake of folic acid
still exist, particularly with respect to cancer.
Why the concern? Folic acid—or rather the bioactive
forms of folic acid (collectively ”folate”)—is required for
de novo synthesis of thymidine, adenine, and guanine,
three of the four nucleotides needed to assemble
DNA. Because cancer cells, like all cells, synthesise
DNA during mitosis, they require a supply of folate.
Limitation of the supply of folate, or inhibition of folate
metabolism (with anti-cancer drugs), slows or arrests
proliferation of several forms of cancer. Conversely, the
supply of cancer cells with extra folate can promote
their proliferation;
thus the concern that increased
folate intake due to folic acid fortifi cation, on top of
dietary and supplemental folate consumption, could
promote existing neoplasms.
The issue is complicated, however, because in non-
cancerous cells, folate can prevent or limit mutational
events that initiate tumorigenic transformation. When
folate is defi cient, the supply of thymidine to insert
into DNA is scarce, resulting in uracil misincorporation.
When uracil is removed, holes are left behind in
the DNA sequence, which ultimately leads to DNA
strand breaks. Additionally, C→T mutations are more
likely to occur when folate is defi cient. Both events
result in DNA damage that can foster tumorigenic
transformation. Thus, folate has a putative two-
faced relationship with cancer: it can protect against
initiation, but promote proliferation.
Is there epidemiological evidence for these dual eff ects
of folate? In 2007, Joel Mason and colleagues
pub lished
a controversial ecological study that suggested colorectal
cancer incidence, which had been decreasing in the USA
and Canada, increased temporarily after the institution of
folic acid fortifi cation in the two countries. Subsequently,
the incidence rate began to decrease again.
One interpretation of these data is that folic acid
fortifi cation enhanced the proliferation and growth
of preclinical neoplastic lesions, making them become
clinically evident, and thus temporarily increasing
apparent incidence. Then, the protective eff ect of folate
against neoplastic initiation kicked in, and incidence
rates declined again. This interpretation has been
challenged, however, by the claim that the increased
incidence occurred too quickly after the start of folic
acid fortifi cation to be biologically plausible.
This is a
speculative statement, however, as the rate of neoplastic
growth can be rapidly modulated by manipulation of
micronutrient supply, at least in cell lines and rodents.
However, empirical data that excess micronutrient con-
sumption in man signifi cantly accelerates neoplastic
growth is lacking, and therefore this point of contention
remains open to debate.
In The Lancet, Stein Emil Vollset and colleagues
present important new data that contribute to the
debate regarding folic acid and cancer. The investigators
conducted a meta-analysis of 13 randomised trials that
Folic acid and cancer—where are we today?
CD is a staff member of WHO. The authors alone are responsible for the views
expressed in this publication, which do not necessarily represent the decisions,
policy, or views of WHO.
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© 2013. World Health Organization. Published by Elsevier Ltd/Inc/BV.
All rights reserved.
Published Online
January 25, 2012
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    • "Osteomyelitis/osteitis is a rare but serious complication of BCG immunization, even in immunocompetent children [1] [2] [3] [4]. Because new TB vaccines in the pipeline have not shown promising results in human trials so far [5], understanding how to best treat BCG complications is extremely important. BCG osteomyelitis/osteitis, typically presents in children 1–2 years after BCG inoculation who develop insidious clinical symptoms/signs despite massive radiologic findings. "
    [Show abstract] [Hide abstract] ABSTRACT: Bacillus Calmette-Guérin (BCG) osteomyelitis/osteitis in immunocompetent children is a rare but serious complication of BCG immunization. Rationale for its treatment is unclear. Due to the rarity of this complication, no randomized control trials has ever been conducted to evaluate methods of intervention. As such, we searched the literature for any reported BCG vaccination-related osteomyelitis/osteitis among immune-competent children published before April 15, 2014. We summarized the data from different affected regions of the body by recording the number of reported cases, while noting outcomes and their medical and/or surgical interventions. From 34 eligible studies gleaned from a screening of 804 articles, a total of 331 cases were enrolled. Involvement of the lower limbs was present in 55.6%, followed by the axial skeleton (26.0%), the upper limbs (15.4%), and multiple bones (3.0%). Of the 64 patients having records of detailed chemotherapy regimens, 45 patients (70%) received two or fewer drugs. Among the 80 patients with detailed surgical records, 50 (62.5%) received surgical procedures for diagnostic purposes. While there were uneventful outcomes for those receiving diagnostic procedures, 7 of the 30 (23.3%) patients receiving surgical interventions had major complications (p=0.002, Fisher's exact test). The overall prognosis was good with a 97.6% cure rate. Nevertheless, eight patients (2.4%) suffered major complications. The rationale for treatment of BCG osteomyelitis/osteitis in immunocompetent children is highly subjective. However, patients receiving diagnostic procedures instead of surgical interventions may avoid major complications. Because only a few of the publications had detailed treatment information, further studies are needed to identify proper treatments, while infant BCG vaccination is still in use. Copyright © 2015. Published by Elsevier Ltd.
    Full-text · Article · Jul 2015
    • "The trial found no protection [8] and led to a lively discussion as to the reasons and implications for this lack of protection [8] [9] [10]. Of particular timeliness, a better knowledge of the mechanism that causes variation in BCG vaccine efficacy might help to explain why MVA85A failed to add to BCG effectiveness in its first trial [8] [9]. The variation in BCG-induced protection cannot be explained by differences in the vaccines strains used or by ethnicity [11] [12]. "
    [Show abstract] [Hide abstract] ABSTRACT: BCG protection varies and in some places (nearest the equator) is low or absent. Understanding this variation can inform the efforts to develop new vaccines against tuberculosis. Two main hypotheses are used to explain this variation: under masking, new vaccines are unlikely to increase protection; under blocking new vaccines have a greater potential to be effective when BCG is not. We conducted a cluster randomized trial to explored the masking and blocking hypotheses by studying BCG vaccine efficacy of neonatal vaccination and when administered for the first or a second (revaccination) time at school age in two sites (Manaus close and Salvador further south from the equator). Seven hundred and sixty three state schools were matched on socio economic characteristics of the neighborhood and 239,934 children were randomized to vaccine (BCG vaccination at school age) or control group. Protection by first BCG vaccination at school age was high in Salvador (34%, 95% CI 7–53%, p = 0.017) but low in Manaus (8%, 95% CI t0 39–40%, p = 0.686). For revaccination at school age, protection was modest in Salvador (19%, 95% CI 3–33%, p = 0.022) and absent in Manaus (1%, 95% CI to 27–23%, p = 0.932). Vaccine efficacy for neonatal vaccination was similar in Salvador (40%, 95% CI 22–54%, p < 0.001) and Manaus (36%, 95% CI 11–53%, p = 0.008). Variation in BCG efficacy was marked when vaccine was given at school age but absent at birth, which points towards blocking as the dominant mechanism. New tuberculosis vaccines that overcome or by pass this blocking effect could confer protection in situations where BCG is not protective. The Department of International Development, UK (DFID) and the National Health Foundation, Brazil (FUNASA) funded the trial. It is registered at Controlled Trials (ISRCTN07601391).
    Full-text · Article · Jun 2014 · BMC Infectious Diseases
    • "In all trials to date, MVA85A induces antigen-specific Th1 and Th17 cells, believed to be important in protection against tuberculosis [9-11]. If, as has been suggested [12], low T cell responses to vaccination in this trial contributed to the lack of vaccine efficacy, understanding the mechanisms determining the magnitude of the response to vaccination is important to the development of an improved vaccine. "
    [Show abstract] [Hide abstract] ABSTRACT: BackgroundTuberculosis (TB) remains a global health problem, with vaccination likely to be a necessary part of a successful control strategy. Results of the first Phase 2b efficacy trial of a candidate vaccine, MVA85A, evaluated in BCG-vaccinated infants were published last year. Although no improvement in efficacy above BCG alone was seen, cryopreserved samples from this trial provide an opportunity to study the immune response to vaccination in this population.MethodsWe investigated blood samples taken before vaccination (baseline) and one and 28 days post-vaccination with MVA85A or placebo (Candin). The IFN-γ ELISpot assay was performed at baseline and on day 28 to quantify the adaptive response to Ag85A peptides. Gene expression analysis was performed at all three timepoints to identify early gene signatures predictive of the magnitude of the subsequent adaptive T cell response using the significance analysis of microarrays (SAM) statistical package and gene set enrichment analysis.ResultsOne day post-MVA85A, there is an induction of inflammatory pathways compared to placebo samples. Modules associated with myeloid cells and inflammation pre- and one day post-MVA85A correlate with a higher IFN-γ ELISpot response post-vaccination. By contrast, previous work done in UK adults shows early inflammation in this population is not associated with a strong T cell response but that induction of regulatory pathways inversely correlates with the magnitude of the T cell response. This may be indicative of important mechanistic differences in how T cell responses develop in these two populations following vaccination with MVA85A.ConclusionThe results suggest the capacity of MVA85A to induce a strong innate response is key to the initiation of an adaptive immune response in South African infants but induction of regulatory pathways may be more important in UK adults. Understanding differences in immune response to vaccination between populations is likely to be an important aspect of developing successful vaccines and vaccination strategies.Trial registrationClinicalTrials.gov number NCT00953927
    Full-text · Article · Jun 2014
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