Universal Vaccines: Shifting to One for Many

Abstract

Human vaccines, with their exquisite antigenic specificity, have greatly helped to eliminate or dramatically abate the incidence
of a number of historical and current plagues, from smallpox to bacterial meningitis. Nonetheless, as new infectious agents
emerge and the number of vaccine-preventable diseases increases, the practice and benefits of single-pathogen- or disease-targeted
vaccination may be put at risk by constraints of timely production, formulation complexity, and regulatory hurdles. During
the last influenza pandemic, extraordinary efforts by vaccine producers and health authorities have had little or no influence
on disease prevention or mitigation. Recent research demonstrating the possibility of protecting against all influenza A virus
types or even phylogenetically distant pathogens with vaccines based on highly conserved peptide or saccharide sequences is
changing our paradigm. “Universal vaccine” strategies could be particularly advantageous to address protection from antibiotic-resistant
bacteria and fungi for which no vaccine is currently available.

Full text

Universal Vaccines: Shifting to One for Many
Antonio Cassone
a
and Rino Rappuoli
b
Department of Infectious, Parasitic, and Immunomediated Diseases, Istituto Superiore di Sanita
`, Rome, Italy,
a
and Novartis Vaccines and Diagnostics, Siena, Italy
b
ABSTRACT Human vaccines, with their exquisite antigenic specificity, have greatly helped to eliminate or dramatically abate the
incidence of a number of historical and current plagues, from smallpox to bacterial meningitis. Nonetheless, as new infectious
agents emerge and the number of vaccine-preventable diseases increases, the practice and benefits of single-pathogen- or
disease-targeted vaccination may be put at risk by constraints of timely production, formulation complexity, and regulatory hur-
dles. During the last influenza pandemic, extraordinary efforts by vaccine producers and health authorities have had little or no
influence on disease prevention or mitigation. Recent research demonstrating the possibility of protecting against all influenza A
virus types or even phylogenetically distant pathogens with vaccines based on highly conserved peptide or saccharide sequences
is changing our paradigm. “Universal vaccine” strategies could be particularly advantageous to address protection from
antibiotic-resistant bacteria and fungi for which no vaccine is currently available.
CURRENT VACCINES: MERITS AND CONSTRAINTS
The current vaccination strategy or “dogma” (1) is that vaccines
prepared to fight a given disease are made by one or a few
specific antigens of the causative microbial agent or its microbial
or viral body with its whole set of antigens. In a few cases, the
vaccine is composed of antigenically related strains belonging to
the same bacterial species or viral family, such as, for instance, the
antituberculous Mycobacterium bovis BCG and smallpox vaccines.
When many different types or clades of the same species can cause
disease (as is, for instance, the case for pneumonia, bacteremia,
and meningitis caused by Streptococcus pneumoniae), the vaccine
may be composed of an unusually high number of antigens rep-
resentative of the most prevalent types or clades (up to 23 poly-
saccharides in the case of the adult vaccine).
There is nothing more to say about these highly specific vac-
cines, focused upon a single pathogen or disease, than to acknowl-
edge their extraordinary merits for the preservation of the health
of populations. Just to cite a few examples, they have helped to
eradicate, eliminate, or control a number of plagues, from small-
pox and polio among the viral illnesses to diphtheria and bacterial
meningitis among the bacterial illnesses. Together with hygienic
water, nothing has probably been more important in the history of
infectious diseases and medicine in general than these vaccines,
particularly in consideration of their benefits versus their costs.
This recognition has led to an ever-increasing appreciation of the
medical and social value of vaccination, thus fostering the gener-
ation of new vaccines that could substantially broaden the spec-
trum of vaccine-preventable diseases. Nonetheless, as the number
of vaccines increases and old and new diseases join the line for a
new vaccine, the practice and benefits of vaccination are being
challenged by several factors that, if taken complacently, could
severely undermine the confidence in the health benefits of vacci-
nation.
When numerous vaccines are used separately, their acceptabil-
ity by the population decreases, as they require an increase in the
number of visits, administrations, side effects, and costs. Further-
more, when a new vaccine is approved, its insertion into the es-
tablished vaccination schedule without affecting compliance with
vaccination may become problematic. The combination of many
different vaccines in a single vial can overcome these issues and has
indeed been successfully achieved for some pediatric vaccines.
Nonetheless, this procedure raises concerns about the preserva-
tion of vaccine quality, long-term stability, and avoidance of neg-
ative interactions among the individual antigens. In addition,
multidose vaccines usually require blending with a preservative to
keep their stability and avoid contamination. The most-used pre-
servative, thimerosal (Merthiolate), continues to be publicly de-
bated for its potential side effects on the nervous system, despite
scientific evidence to the contrary. Finally, combination vaccines
may not be suitable for poor countries and may not be able to keep
up with rapid epidemiological changes. Overall, it is hard to imag-
ine that putting all of the needed vaccines together in a single vial
can be a solution for the future.
Particular problems arise when the vaccine target is a microbe
or a virus spread in nature as multiple variants (serogroups, sero-
types, clades, etc.), all causing the same infections. This is a chal-
lenge, for instance, with both the meningococci and still more
with pneumococci (2). In the case of Streptococcus pneumoniae,91
capsular serotype variants are known, and although most of them
are infrequent causes of disease in humans, the number of infec-
tious types remains high. The 23-polysaccharide vaccine generates
opsonic antibodies directed against serotype-specific capsular
polysaccharides and is safe and protective but does not immunize
⬍2-year-old children (an age range that includes a high propor-
tion of the most severe cases of pneumococcal bacteremia and
meningitis). In addition, its efficacy in immunocompromised pa-
tients is quite inconsistent. Glycoconjugate vaccines have been
generated with the capsular polysaccharides of the most wide-
spread and aggressive S. pneumoniae serotypes. They induce
T-cell-dependent immunity and opsonizing antibodies directed
against type-specific capsular polysaccharides even in very young
children (2). These vaccines are also safe and highly protective
against invasive S. pneumoniae infections, but serotype shifting
may elude the antibody response and displace the vaccine strain. A
Published 18 May 2010
Citation Cassone, A., and R. Rappuoli. 2010. Universal vaccines: shifting to one for many.
mBio 1(1):e00042-10. doi:10.1128/mBio.00042-10.
Copyright © 2010 Cassone and Rappuoli. This is an open-access article distributed
under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0
Unported License, which permits unrestricted noncommercial use, distribution, and
reproduction in any medium, provided the original author and source are credited.
Address correspondence to Antonio Cassone, cassone@iss.it.
PERSPECTIVE
April 2010 Volume 1 Issue 1 e00042-10 mbio.asm.org 1

major event of this kind has been the replacement of vaccine se-
rotypes with nonvaccine serotype 19A, a serotype of S. pneu-
moniae that is prevalent worldwide, is clinically important, and
has the potential for multidrug resistance (2, 3). Thus, we are in a
continuous and breathless race, chasing an elusive and dreadful
threat with the best of our current glycoconjugate technology to
increase the number of vaccine constituents and ensure an effi-
cient formulation. However successful, all of this requires cum-
bersome and costly reformulation of the vaccine from time to
time, with an obvious upper limit.
Fortunately, pneumococcal vaccines do not change every year,
as influenza vaccine does! The latter probably constitutes an ex-
treme example of the limitations posed by vaccines with highly
focused specificity. Owing to the high variability of its main anti-
genic constituents inducing neutralizing antibodies (i.e., hemag-
glutinin [HA] and neuraminidase, glycoproteins of the viral en-
velope), annual reformulation of a previous vaccine or simply the
generation of a totally new one is needed to achieve sufficient
protection of the population against the changing threat. Vaccine
production, testing for effectiveness, approval by regulatory bod-
ies, distribution, and use require something approaching 1 year, a
time frame that can make the vaccine useless. The severe limita-
tions of this situation are most acutely apparent when a new pan-
demic virus, spreading globally in few weeks, emerges: in the last
three influenza pandemics (1957, 1968, and the 2009 ongoing
one), when a vaccine could be and was indeed produced, the im-
pact, if any, of vaccination on disease prevention or mitigation has
been low (4; http://www.who.int). This is particularly frustrating
when, as in the last influenza A (H1N1) 2009 pandemic, the oc-
currence of a new pandemic had long been anticipated, sustained
efforts by public health authorities and international scientific or-
ganizations were brought to the highest possible preparedness
level, and vaccine manufacturers were forced to make a major,
unprecedented technological and resourceful effort to produce a
vaccine as rapidly as possible.
INFLUENZA: RUSHING TO UNIVERSALITY
To confront these remarkable problems, various options and
technological advances for the more rapid production of vaccines
are being pursued, and these will clearly help. Nonetheless, it is
unlikely that the challenge will be met exclusively by technology,
since this also requires an evolution of our approach to vaccine
generation aimed at identifying commonalities in a world of an-
tigenic diversity. With specific reference to influenza, it has long
been suspected that a solution could come from the identification
of highly conserved sequences in the viral genome and the con-
struction of a vaccine accordingly. In this launching issue of mBio,
Steel et al. (5) provide an example of the application of the above-
described concepts and technical advances by demonstrating that
a vaccine based on a highly conserved sequence of the HA stalk
region elicited cross-protective antibodies and was broadly pro-
tective in a murine influenza model. This follows a number of
older and more recent contributions identifying human antibod-
ies generated by immunization with inactivated seasonal influ-
enza vaccine or just screened from combinatorial antibody librar-
ies, which were cross-reactive with such distant H1 and H5 HAs.
These monoclonal antibodies bound to a conserved epitope of the
nonglobular portion of the HA molecule close to or containing the
fusion peptide (6). Previously, other regions of the influenza virus,
pertaining to either the nucleoprotein or the M2 protein of the
pericapsidic virus membrane, had been identified; these regions
contain highly conserved sequences suitable, in principle, for the
generation of cross-protective antibodies and cell-mediated im-
munity. This may occur especially when the antigenic construct is
linked to ligands of Toll-like receptors for efficient stimulation of
innate immunity (7–10). In this regard, it is of interest that better
coverage of influenza can be obtained by the use of oil-in-water
adjuvants, such as MF59 and ASO3, which have turned out to be
potent stimulators of innate immunity (11). In a recent work, it
has been shown that MF59 may render highly immunodominant
also those epitopes which are of low intrinsic dominance when
other adjuvants are used (12), thus helping to induce strong spe-
cific antibody responses. Figure 1 schematically summarizes the
path of influenza vaccine progress. Traditionally, we have had to
use a different vaccine for every single virus variant; however,
today we can protect against a subgroup of strains by using an
adjuvanted vaccine able to cover the diversity of closely related
viruses. It is hoped that, in the near future, universal vaccines will
be the final solution to pandemic and seasonal influenza.
RESTRICTED UNIVERSALITY: A PRACTICAL SOLUTION FOR
VACCINES AGAINST A DEFINED SPECIES OR GROUP OF
PATHOGENS
Is influenza the only disease that warrants approaches for univer-
sal vaccines? Clearly, it is not, as the call to extend this vaccination
practice to all diseases that need it justifies many other instances
where approaches to universal vaccines, meaning sustained efforts
FIG 1 Schematic representation of the progress in the development of vac-
cines against the most recent pandemic and seasonal H1N1 influenza virus
strains. The use of adjuvants already allows the coverage of closely related
strains with one vaccine. In the future, a universal vaccine may cover all strains.
Perspective
2mbio.asm.org April 2010 Volume 1 Issue 1 e00042-10

to identify common antigenic determinants of types or clades and
generate vaccines based on these commonalities, are pursued.
Nowadays, the application of this “universality” strategy to vac-
cines for many other diseases has come out of the clouds of pure
empiricism and has been made realistic by the enormous progress
made in genomic research, particularly by whole-genome se-
quencing, reverse genetics, and vaccinology and the use of com-
binatorial antibody libraries and recombinant DNA technology.
The ability to sequence the genomes of microorganisms has been
a quantum leap in the ability to mine the microbial blueprint and
discover conserved antigens that could not be identified by other
technologies. Contributory is also the extensive use of more classic
biochemical techniques, particularly with polysaccharides and
glycoconjugate technologies, with all of this blended with the ex-
traordinary advances in the knowledge of receptors, ligands, and
mechanisms of innate and adaptive immunity (6, 11).
The case for a universal pneumococcal vaccine has already
been discussed. A promising approach is one based on a combi-
nation of a few highly conserved pneumococcal proteins, inclusive
of the pneumolysin derivatives and some cell surface proteins.
Examples of broad serotype protection with these protein-based
vaccines have been obtained in experimental models (3). A me-
ningococcal vaccine immunizing against all serogroups, including
serogroup B, against which there is no available vaccine, is also
being addressed (13). With the aim to overcome the high diversity
of HIV, a universal vaccine based on a chimeric protein encom-
passing the 14 most conserved HIV regions, inserted into efficient
viral vectors, has been designed and tested in preclinical models
(14). A universal vaccine strategy to fight the heterogeneity of
arenavirus causing severe human infections has recently been pro-
posed (15). In all of the cases mentioned above, we are dealing
with somewhat “restricted universality,” since the vaccines are
intended to protect against defined, closely related members of a
species or family of infectious agents.
UNRESTRICTED UNIVERSALITY: SOMETHING OF A DREAM
Other, less restricted instances of “universality” with much
broader applications and consequences also deserve careful con-
sideration in view of the encouraging preliminary results. They
suggest that the “universality” strategy could be particularly ap-
pealing, and feasible, for the generation of a vaccine against the
large group of bacteria and fungi for which there is so far no
vaccine at all.
A prominent one is made up of bacteria that mostly cause
health care-associated infections. There is no vaccine against bac-
teria such as Staphylococcus aureus,Escherichia coli,Pseudomonas
spp., and Acinetobacter baumannii, which together are responsible
for the majority of the infections mentioned above, ranging from
septicemia to pneumonia and urinary tract infections, with mil-
lions of cases worldwide and elevated mortality despite antibiotic
use (16). Adding to the threat, these bacteria often convey a wide
array of antibiotic resistance traits and some strains of A. bauman-
nii are actually resistant to almost all of the antibiotics in use.
Species variants and types of these bacteria and the virulence fac-
tors possessed by each of them are so numerous and diverse that it
is quite unlikely to be possible to have specific vaccines. Recently,
a glycoconjugate of a synthetic, deacetylated beta-(1-6)-linked,
N-acetylated oligoglucosamine polysaccharide (poly-N-acetyl-
glucosamine) which is shared by practically all of the bacteria
listed above has been shown to induce antibodies that opsonize
and kill both S. aureus and E. coli and protect against infections by
these two bacteria in reliable experimental models (17).
Special attention should also be focused on fungal infections,
the most widespread of which (for instance, aspergillosis, crypto-
coccosis, and invasive candidiasis) typically occur in the setting of
immunocompromised patients. Moreover, species of the genus
Candida, the most frequent agents of fungal infections, are human
commensals and species of the genus Cryptococcus can establish a
latent host infection. Immunoevasion can occur through antigen
target restriction, immunodepression, latency, and commensal-
ism, which are all conditions that raise remarkable obstacles to
vaccination against each single agent or species (18). The perspec-
tive would clearly change if we could make available a vaccine
protective against all of the main fungal agents in patients who
share almost overlapping risk factors (e.g., neutropenia) and
could therefore be vaccinated before they became debilitated and
immunocompromised. Our approach to a universal vaccine
against opportunistic fungal pathogens relied on the use of lami-
narin, a beta-glucan from algae, which was conjugated with a ge-
netically detoxified diphtheria toxin and used to immunize and
protect from both Candida and Aspergillus fungi (19). The anti-
beta-glucan antibodies generated by the above vaccination and
monoclonal antibodies sharing that specificity proved to be pro-
tective also against Cryptococcus (20). Importantly, all of these
antibodies showed a direct inhibitory activity against the three
pathogens in the absence of host cells. Directly inhibitory antibod-
ies are uncommon and may have advantages for use in immuno-
compromised patients. An approach with an even wider purpose
is so-called “idiotypic vaccination” (21). This is based on immu-
nization with an antibody directed against a wide-spectrum yeast
killer toxin to raise anti-idiotypic antibodies that mimic the fun-
gicidal activity of the killer toxin itself. Further support for these
universal vaccine approaches comes from recent investigations
showing that a vaccine composed of heat-killed yeast (Saccharo-
myces cerevisiae) cells is protective against coccidiomycosis, be-
sides candidiasis (22, 27; Cassone et al., unpublished data). Still
more remarkable is the approach taken by some researchers to
generate protective immunity against both Candida albicans and
Staphylococcus aureus (two top-ranking causes of health care-
associated infections) by the use of a vaccine based on the Candida
adhesin Als3 (23, 24).
CONCLUSIONS, PERSPECTIVES, AND CRITICAL ISSUES
There is now hope, sustained by knowledge and technology, for
the generation of broadly protective “universal” vaccines re-
stricted to species or groups of closely related pathogens or even
cross-family or -kingdom vaccines. Overall, it is time to address a
new strategy for vaccination based on antigenic commonalities for
cross-protective vaccine production. Of particular interest is the
fact that some highly conserved universal sequences such as those
present in cell surface or cell wall polysaccharides such as beta-
glucan are well-known “pathogen-associated molecular patterns”
(PAMP) which are sensed by a host’s innate immune system, with
a cascade of immunologic events leading to the activation of an-
timicrobial effectors and antigen-presenting cells which ulti-
mately determine the fate of antigen-specific adaptive immunity.
In theory, PAMP-based vaccines could suitably merge the two
phases of immune responses for optimal anti-infectious protec-
tion in a way expressing the immunizing potency of an adjuvant-
antigen mixture in the same molecule (8, 25).
Perspective
April 2010 Volume 1 Issue 1 e00042-10 mbio.asm.org 3

Beta-glucan-based fungal vaccines can generate fungicidal or
fungus growth-inhibitory antibodies (18, 19). Theoretically, bac-
tericidal antibodies could be raised by immunization with func-
tionally similar, highly conserved PAMP such as, for instance,
peptidoglycan fragments, alone or conjugated to a carrier. These
antibodies would act as antibiotics, and Polonelli and collabora-
tors have coined the term “antibiobodies” for them (26). These
antibodies could be a breakthrough in the therapy of immuno-
compromised patients.
Nonetheless, universal vaccines carry some potential limita-
tions and constraints that must be identified and overcome for
their rational exploitation. The first and somewhat obvious one is
some defocusing of the immune responses and then a decrease in
the capacity to eliminate or keep at bay the etiologic agent. Uni-
versal sequences may not be immunodominant, raising the issue
of how to potentiate the dominance of antigenic determinants
without excessive inflammation. The use of potent viral vectors,
presentation as virus-like particles, conjugation with highly im-
munogenic carriers, and formulation with improved adjuvants
such as oil-in-water mixtures or PAMP are some of the tools being
exploited. All of the above, in particular the use of PAMP either as
an antigen or as a carrier, conveys the possibility of raising auto-
immune responses through molecular mimicry or even raising
immune responses which dampen the host’s capacity to recognize
FIG 2 Schematic view of the history, progress, and perspective of universal vaccines and the accompanying technological tools that make that progress feasible.
Perspective
4mbio.asm.org April 2010 Volume 1 Issue 1 e00042-10

molecular pattern signatures for a first-line antimicrobial defense.
Finally, these broadly specific immune responses might strongly
affect the human microbiota, causing excessive elimination of in-
nocent bystanders. Thus, a careful dissection of host beneficial
immunity from harmful responses is necessary. Nonetheless, we
should not be deterred from in-depth exploration of what is com-
mon to a defined type, species, or group of microorganisms, even
if they are very distantly related, to move ahead our current strat-
egy of vaccination. Figure 2 schematizes the vaccine history and
perspective that are leading those working with vaccines from a
merely empirical microbiological stage to a future one which
promises to use the best of our “-omics” to generate vaccines using
single antigens to protect against many diseases caused by genet-
ically related or even very dissimilar pathogens.
ACKNOWLEDGMENTS
We thank Annalisa Pantosti and Antonella Torosantucci (ISS, MIPI De-
partment) for reading the manuscript and helpful discussions.
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