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Introduction
Editorial overview
Hildegund CJ Ertl and Antonio Lanzavecchia
Current Opinion in Immunology 2010, 22:355357
0952-7915/$ see front matter
# 2010 Elsevier Ltd. All rights reserved.
DOI 10.1016/j.coi.2010.05.001
Hildegund CJ Ertl
Wistar Institute, 3601 Spruce Street,
Philadelphia, PA 19104, USA
e-mail: ertl@wistar.upenn.edu
Gundi Ertl, MD, is a professor,
Chair of the Immunology
Department and director of the
Vaccine Center at the Wistar
Institute with adjunct appointments
at the University of Pennsylvania
and the Childrens Hospital of
Philadelphia. Her lab works on the
development of viral vector based
vaccines to HIV-1, rabies and
influenza virus, and viruses
associated with cancer. In addition
she is studying complications of
long-term gene replacement
therapy by adaptive immune
responses to gene transfer vehicles.
Antonio Lanzavecchia
Institute for Research in Biomedicine, Via
Vincenzo Vela 6, CH-6500 Bellinzona,
Switzerland
e-mail: lanzavecchia@irb.unisi.ch
Antonio Lanzavecchia, MD, has
been a member of the Basel
Institute for immunology from 1983
to 1999 and is currently the
founding director of the Institute for
research in Biomedicine in
Bellinzona, Switzerland and
professor of Human Immunology at
the Swiss Federal Institute of
Technology Zurich. He worked on
different aspects of human
immunology: antigen processing
and presentation, dendritic cell
biology, T and B cell activation, and
immunological memory.
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Introduction
Since 1796, when Jenner first inoculated a young boy with cow poxvirus and
thereby rendered him resistant to a subsequent challenge with smallpox
virus, an experiment that today would most certainly not be approved by
regulatory agencies, vaccines have been developed to many of the prevailing
viral and bacterial infections. Vaccines not only save lives at a comparatively
low cost but they have also succeeded in eradicating smallpox virus that in
the 20th century killed an estimated 300500 millions of humans and in the
future they could eliminate other pathogens that require humans as an
essential host. Although by now in 2010 a total of 64 vaccines have been
licensed in the US against 25 different pathogens or their toxins, significant
scientific challenges remain. At the same time advances in immunology and
molecular biology offer an unprecedented array of opportunities to develop
vaccines to not only prevent infectious diseases but also avert or cure chronic
infectious diseases as well as other not infectious diseases such as cancer,
Alzheimer, or hypertension.
In spite of worldwide vaccination programs, infectious diseases such as
respiratory infections, diarrheal diseases, HIV/AIDS, tuberculosis, and malaria
continue to cause worldwide nearly a quarter of all human death and a total of
1.5 billion disability-adjusted life years (DALYs), defined as the loss of healthy
life [1]. Despite intensive scientific efforts, efficacious vaccines remain elusive
for some of the most devastating pathogens such as HIV-1 and plasmodium
falciparum or vivax while others such as vaccines to mycobacterium tubercu-
losis lack efficacy. Many vaccines require adjuvants and currently only alum-
derived adjuvants, which are frequently far from optimal are licensed in the
US, while in addition MF-59, a submicron oil-in-water emulsion of a squalene,
polyoxyethylene sorbitan monooleate and sorbitan trioleate is approved for
use in some vaccines in Europe and other countries. With our rapidly
increasing knowledge on pathways that drive or inhibit activation of adaptive
immune responses, novel adjuvants that either augment immunostimulatory
or block immunoinhibitory pathways can be designed that not only influence
the magnitude but also the flavor of antigen-driven immune responses.
In this volume we describe novel approaches to develop vaccines to three of
the major infectious diseases, that is, tuberculosis, malaria, and AIDS and to
non-communicable diseases such as cancer, degenerative diseases, or auto-
immunity. Prevention of infections by some of the more complex pathogens
as well as cure of chronic infections or cancer requires induction of potent
CD8+ T cell responses that become impaired upon prolonged antigen
exposure; thus one chapter focuses on induction of CD8+ T cell responses
while two other chapters address the role of immunoinhibitory pathways in
the induction of immune responses. Two additional chapters address new
adjuvants based on agonists of Toll-like receptors or invariant NKT cells.
Current Opinion in Immunology 2010, 22:355357
356 Vaccines
HIV-1/AIDS
Most licensed vaccines induce protection through neu-
tralizing antibodies. The envelope protein (Env) of HIV-
1, the virus sole target for neutralizing antibodies, is
extraordinarily variable, heavily glycosylated and under-
goes structural changes upon receptor binding [1,2]. It has
thus been impossible so far to design Env-based immu-
nogens, which can induce antibodies that reliably neutral-
ize a broad spectrum of different HIV-1 isolates. Recent
HIV-1 vaccine efforts have thus largely focused on induc-
tion of T cell responses most notably CD8+ T cells to
HIV-1. The failure of a large-scale phase IIb trial (STEP
trial) designed for induction of T cells to HIV-1 through
an adenovirus (Ad) vector of human serotype 5 (AdHu5)
casted doubt on the concept of T cell-mediated protec-
tion against HIV-1 [2] that were reinforced by results of
the RV 144 trial in which the vaccine induced only low T
cell responses and mainly non-neutralizing antibodies to
Env but nevertheless showed a reduction of HIV-1 in-
fection rates [3] suggesting that antibodies to Env may be
essential to prevent an HIV-1 infection. The chapter by
L. Walker and D. Burton describes recent results on the
complex structure of HIV-1 Env proteins, novel tech-
niques for isolation of broadly neutralizing antibodies and
pathways of antibody-mediated protection thus providing
guidance to a rational HIV-1 Env-based vaccine design.
Malaria
Although numerous malaria vaccines have undergone
early clinical testing only one, the so-called RTS,S
vaccine composed of an adjuvanted recombinant circum-
sporozoite protein together with recombinant hepatitis B
surface antigen has reached phase 3 testing after showing
30% efficacy in children aged 14 [4]. Infection with
Plasmodium itself can induce resistance against parasi-
temea but fails to elicit lifelong sterilizing immunity,
which may partly be linked to the parasites ability to
compromise activation of CD8+ T cells. The chapter by
Sauerwein et al. discusses some of the immunosubvesive
strategies of plasmodium and proposes the use of drugs
such as chloroquine, which not only kills parasites in their
asexual blood stage but also has immunomodulatory
functions in combination with attenuated sporozoites as
a vaccine strategy.
Tuberculosis
While most current vaccines are based on antibody
responses, a tuberculosis vaccine is expected to act mainly
through induction of cell-mediated immunity. The
design of a vaccine with improved efficacy as compared
to the currently available attenuated BCG vaccine
represents a major challenge, especially in view of the
difficulties in the identification of the correlates of pro-
tection. The chapter by Parida and Kaufmann provides a
comprehensive review of the biology of mycobacterial
infection and of the strategies used and obstacles to
design improved vaccines. The review also offers an
Current Opinion in Immunology 2010, 22:355357
update on the current status of the eleven tuberculosis
vaccines that are in various phases of clinical trials.
Cancer
Active immunotherapy of cancer remains an elusive holy
grail of oncologists although the successes of adoptive
transfer studies of patient-derived ex vivo-expanded
tumor-specific CD8+ T cells has provided ample evi-
dence that the immune system is capable to eliminate
even large tumor masses [5]. The commonly observed
lack of efficacy of traditional cancer vaccines may relate to
the tumors ability to subvert immune responses by
augmenting immunoinhibitory pathways. The chapter
by Lasaro and Ertl discusses the use of vaccines directed
against tumor-associated antigens in combination with
reagents that inhibit the immunoinhibitory pathways that
are evoked during tumor progression.
Non-communicable diseases
Chronic non-infectious diseases such as hypertension,
inflammatory diseases, autoimmunity, or neurodegenera-
tion are afflicting an ever increasing segment of the
human population being especially common in the aged
whose immune system is impaired by immunosenes-
cence. As discussed by M. Bachmann, vaccines can be
designed to induce auto-reactive antibodies to disease-
associated self-proteins without breaking T cell tolerance
by expressing self B cell epitopes together with foreign T
helper cell epitopes. Several vaccines based on this prin-
ciple are now in clinical trials including those directed
against amyloid b for treatment of Alzheimer, angiotensin
I or II for therapy of hypertension, and TNF-a or IL-1b to
counterbalance autoimmune diseases.
The PD1 pathway
Both positive and negative signals regulated T cell
responses to infections or vaccination. PD-1, upon inter-
action with its ligands PD-1L1/2 has been studies exten-
sively for its inhibitory role during chronic infections
where T cells differentiate towards exhaustion [6]. The
chapter of Brown et al. describes the emerging roles of
PD-1/PD-L1/2 in primary immune responses where
these pathways act on multiple cells of the immune
system including T and B lymphocytes and cells of the
innate immune system. Intriguingly, depending on cir-
cumstances PD-1 pathways not only provide inhibitory
signals but may also serve to enhance immune responses.
Rational CD8+ T cell vaccine design
Designing vaccines that elicit effective CD8+ T cell
responses against viruses and tumor cells requires a
detailed understanding of the pathways of antigen pres-
entation in vivo. The chapter by Jonathan Yewdell offers a
compelling and entertaining overview of the basic prin-
ciples that govern the CD8+ T cell responses in vivo and
discusses these principles in the context of a rational
vaccine design. Among other aspects this review
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addresses the mechanisms and role of cross-priming, its
pharmacological regulation and its recent successful
application to peptide-based CD8 T cell vaccine that
showed remarkable clinical efficacy in HPV-associated
neoplasias [7].
iNKT cell agonists as vaccine adjuvants
Invariant natural killer T cells (iNKT cells) recognize
glycolipids presented by the invariant class I like mol-
ecule CD1d [8]. These cells possess effector function and
represent an abundant source of T cell help that can be
rapidly mobilized in all individuals. Cerundolo and co-
workers review recent studies that led the ground to the
use of iNKT cell ligands as adjuvants capable of enhan-
cing dendritic cell and B cell activation. Microspheres
containing antigen and iNKT cell ligands of appropriate
strength act as effective immunogens by ensuring effec-
tive delivery of antigen and T cell help to antigen specific
B cells in vivo. Thus iNKT cell agonists represent a new
class of adjuvants that exploits an abundant population of
already activated effector T cells.
Summary
Rational vaccine design remains a long sought and ambi-
tious goal. While animal studies have been extremely
important to unravel the fundamental mechanisms that
govern the immune response, we are still facing the chal-
lenge of understanding the human immune system in its
complexity and genetic heterogeneity and in unraveling
the sophisticated escape mechanism used by human patho-
gens. In spite of obvious limitations in human experimen-
tations and clinical trial, the twenty first century
vaccinologists can take advantage of new tools and exper-
imental approaches to identify the mechanisms of protec-
tion as well as the antigens that are target of protective
responses. The formulation of these antigens together with
new adjuvants capable of eliciting strong and durable
immune responses of the appropriate class will be the basis
for the design of a panoply of vaccines that will be able to
deal effectively with a variety of threats to human health.
New adjuvants
The immunogenicity of vaccines can be augmented by
the addition of adjuvants that in general initiate a non-
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Editorial overview Ertl and Lanzavecchia 357
specific inflammatory reaction. The number of currently
licensed adjuvants is very limited and those that are
available are no necessarily optimal for a given appli-
cation. Recent advances in our understanding of pathways
that regulate activation of cells of the innate immune
system now allow for a more informed approach to
develop new adjuvants. The chapter of Mbow and col-
leagues describes already licensed adjuvants as well as
adjuvants based primarily on Toll-like receptor agonists
that are undergoing clinical or pre-clinical testing.
References and recommended reading
Papers of particular interest, published within the annual period of
review, have been highlighted as:
 of special interest
 of outstanding interest
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Miranda ME, Shaw A, Zinsstag J, Meslin FX: Re-evaluating the
burden of rabies in Africa and Asia. Bull World Health Organ
2005, 83:360-368.
2. Buchbinder SP, Mehrotra DV, Duerr A, Fitzgerald DW, Mogg R,
Li D, Gilbert PB, Lama JR, Marmor M, Del Rio C et al.: Efficacy
assessment of a cell-mediated immunity HIV-1 vaccine (the
Step Study): a double-blind, randomised, placebo-controlled,
test-of-concept trial. Lancet 2008, 372:1881-1893.
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6. Kenter GG, Welters MJ, Valentijn AR, Lowik MJ, Berends-van der
Meer DM, Vloon AP, Essahsah F, Fathers LM, Offringa R,
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7. Freeman GJ, Wherry EJ, Ahmed R, Sharpe AH: Reinvigorating
exhausted HIV-specific T cells via PD-1-PD-1 ligand blockade.
J Exp Med 2006, 203:2223-2227.
8. Salio M, Silk JD, Cerundolo V: Recent advances in processing
and presentation of CD1 bound lipid antigens. Curr Opin
Immunol 2010, 22:81-88.
Current Opinion in Immunology 2010, 22:355357