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THE BURDEN OF INFECTION EARLY
More than 2 million newborns and infants
under the age of 6 months die each year
worldwide from infection (1–3). In this
context, vaccines are second only to clean
drinking water as a cost-ef ective measure
to reduce infant morbidity and mortal-
ity. Global eradication of smallpox and
the hopefully forthcoming eradication of
poliomyelitis demonstrate the power and
potential of immunization programs. Per
World Health Organization (WHO) guide-
lines, children should be immunized with
Bacille Calmette-Guérin (BCG) to prevent
disseminated tuberculosis in endemic areas,
as well as Diphtheria, Tetanus, and Pertus-
sis (DTaP); oral or inactivated Polio vaccine
(OPV or IPV, respectively); hepatitis B vac-
cine (HBV); measles vaccine; and Haemoph-
ilus inf uenzae type b (Hib) vaccine (4).
However, substantial morbidity and mortal-
ity among neonates and infants continues to
be caused by infections, including those that
are currently vaccine-preventable. Common
pathogens of infants include Streptococcus
pneumoniae, H. inf uenza, Escherichia coli
and other enteric Gram-negative bacteria,
Bordetella pertussis (whooping cough), as
well as Herpes Simplex Virus, Respiratory
Syncitial Virus, and rotavirus (5). T is bur-
den of infection highlights early-life sus-
ceptibility, particularly among those 0 to 6
months of age, and an unmet global need for
Developing new vaccines against patho-
gens, such as respiratory syncitial virus
(RSV), malaria, HIV, and Dengue virus, as
well as enhancing availability and delivery
of existing, available vaccines could help
mitigate the global burden of infection.
However, any such approaches will need to
focus on early-life immunization in order
to benef t the very young, including new-
borns, def ned as those who are ≤28 days
of age. Immunization of pregnant mothers,
with the consequent, passive transplacen-
tal transmission of antibodies to the fetus,
could protect neonates (6). However, this
promising strategy might be limited by
safety and medico-legal concerns. Because
birth is the most reliable point of health care
contact worldwide, vaccines that are active
at birth are of special and strategic impor-
tance (7). Vaccines given at birth achieve
high population penetration and could sub-
stantially reduce the window of susceptibil-
ity inherent to the current vaccine schedules
that largely focus on a 2/4/6 months of age
schedule (Table 1) (8).
VACCINES CURRENTLY LICENSED FOR
USE AT BIRTH
On a global basis, three vaccines are current-
ly licensed for immunization at birth: HBV,
BCG, and OPV. Of these, only the HBV
vaccine is given in the United States, with a
f rst dose at birth (Table 1). As with many
medications, these were f rst developed for
and tested in older individuals and then
eventually evaluated in newborns. Clinical
trials that investigated an accelerated vacci-
nation schedule of these vaccines, including
neonatal “birth” doses, demonstrated safety
as well as ef cacy, of en as ref ected by the
production of antigen-specif c antibodies, a
surrogate marker of protection (Table 2).
Hepatitis B vaccine. T e rates of tuber-
culosis in the United States are suf ciently
low so that BCG is not indicated for neo-
nates and polio immunization is provided as
IPV beginning at 2 months of age; therefore,
HBV is the only vaccine administered dur-
ing the f rst 28 days of life that is currently
recommended in the United States (Table 1)
(8). HBV vaccine, available since 1982, uses
recombinant DNA technology to express
hepatitis B surface antigen—a protein that
forms viral-like nanoparticles—in yeast.
Alum, a chemical compound containing
aluminum salts whose mechanism of action
is still under investigation (9), is added as
adjuvant. A three-dose series of HBV start-
ing at birth is safe and ef ective (10).
Bacille Calmette-Guérin. Having been
administered to more than 3 billion people,
BCG is the most commonly used vaccine
worldwide (11). BCG is a single-dose vac-
cine of freeze-dried, live Mycobacterium
bovis. T e BCG vaccine does not contain
any exogenous adjuvant but is intrinsically
“self-adjuvanted” because Mycobacteria
activate immune responses via transmem-
brane Toll-like receptors (TLRs), including
TLR-2, -4, and -8 (12). Although newborns
typically demonstrate impaired T helper
1 (T 1) immunity to multiple stimuli, re-
markably, BCG can induce T 1-polarizing
immune responses at birth (13). BCG has a
good safety prof le and has been estimated
to prevent approximately 30,000 cases of tu-
berculous meningitis and ~11,500 cases of
miliary disease during the f rst 5 years of life
(14). Of note, BCG administration to new-
borns appears to have a benef cial ef ect on
survival not solely ascribable to protection
against tuberculosis, raising the possibility
that this live-attenuated vaccine may have
benef cial immune-enhancing ef ects (15).
Oral polio vaccine. In the United
States, polio immunization begins with a
dose of IPV at 2 months of age. In contrast,
in countries where poliomyelitis has not yet
been controlled, the Sabin OPV—compris-
ing live-attenuated poliovirus Sabin strains
1, 2, and 3—is administered at birth as a
single dose to prevent poliomyelitis and
promote herd immunity (16). Although T
cell IFN-γ and proliferative recall responses
to OPV are limited af er immunization at
birth, OPV does induce protective antibod-
ies in neonates (17). Of note, there is no ex-
trinsic adjuvant added with OPV, although
it contains single-stranded RNA—a class of
molecules that can activate human cells via
VACCINES TESTED AT BIRTH OR
Investigators have recognized that immu-
nization at birth represents a practical ap-
Development of Newborn
and Infant Vaccines
Guzman Sanchez-Schmitz1,2 and Ofer Levy1,2*
*Corresponding author. E-mail: ofer.levy@childrens.
1Children’s Hospital Boston, Boston, MA 02115, USA.
2Harvard Medical School, Boston, MA 02115, USA.
Vaccines for early-life immunization are a crucial biomedical intervention to reduce global
morbidity and mortality, yet their developmental path has been largely ad hoc, empiric,
and inconsistent. Immune responses of human newborns and infants are distinct and can-
not be predicted from those of human adults or animal models. Therefore, understanding
and modeling age-specif c human immune responses will be vital to the rational design
and development of safe and ef ective vaccines for newborns and infants.
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proach to reducing the global burden of
infection, and, accordingly, several studies
have evaluated vaccines in newborns [re-
viewed in (19)]. A few important examples
are highlighted here and in Table 2.
Pertussis. B. pertussis is the etiologic agent
of whooping cough that still claims the lives
of hundreds of thousands of infants world-
wide and has been responsible for a recent
outbreak in California, resulting in the deaths
of many infants, most of whom were less than
2 months of age at disease onset (20). T e
particular severity of this infection in young
infants has motivated studies of neonatal im-
munization against this pathogen (Table 2).
Studies of neonatal pertussis immunization
dating back to the 1940s indicate safety of
immunization against pertussis at birth, but
with variable ef cacy (21). Using a whole-cell
vaccine, immunization within 24 hours of
life resulted in inadequate serum titers (22).
A series starting at 1 week, continuing at 5
and 9 weeks, and followed by a booster at 6
to 12 months, resulted in protective pertus-
sis agglutinin levels in only ~60% of infants
(20). Immunization starting at 3 weeks of life
was apparently ef ective (23), possibly ref ect-
ing age-dependent maturation of antigen-
presenting cell and lymphocyte function.
Whole-cell pertussis preparations have
been associated with reactogenicity, includ-
ing erythema and local inf ltration as well as
fever and irritability (24), which prompted
the development of acellular pertussis (aP)
vaccines containing toxoid, f lamentous
hemagglutinin (fHA), pertactin, and f m-
briae-2 and -3. However, when given in con-
junction with DTaP starting at 2 to 14 days
of age aP vaccination resulted in a lower
antibody response to diphtheria and to mul-
tiple pertussis antigens as compared with
infants receiving the vaccine at 2/4/6/17
months only (25). T ese observations sug-
gest vaccine interference, in which simul-
taneous administration of multiple vaccine
antigens may interfere with one another’s ef-
f cacy. Such antagonistic interactions could
ref ect, for example, inhibition of antigen
presentation and/or B lymphocyte prim-
ing—steps that are key for Ab formation.
Nevertheless, aP vaccines have proven safe
in newborns and have resulted in enhanced
immune responses when given initially as
the aP vaccine alone followed by DTaP at
3/5/11 or 2/4/6 months (26), an approach
that has been associated with T 2 polariza-
tion of infant cellular immune memory (27).
Pneumococcus. A trial based in Papua
New Guinea evaluated neonatal immuni-
zation with a seven-valent pneumococcal
conjugate vaccine comprising pneumococcal
polysaccharides coupled to the CRM197 car-
rier protein [a nontoxic variant of diphtheria
toxin isolated from cultures of Corynebacte-
rium diphtheriae strain C7 (β197)] adjuvant-
ed with Alum, named PCV7 (28). At birth,
PCV7 was immunogenic, but associated with
somewhat lower antibody titers to multiple
serogroups at 4 months of age (29). Infants
that had received a dose of PCV7 at birth
subsequently had greater T 2 polarization of
TLR-mediated cytokine responses in vitro,
suggesting a possible ef ect on subsequent
immune system polarization (28).
Rotavirus. Rotavirus causes hundreds
of thousands of infant deaths worldwide.
An immunization schedule initiated in
the neonatal period (2 to 7 days of age) as
a 0/2/4 or 0/2/6 months schedule with live
oral rhesus-human reassortant rotavirus tet-
ravalent vaccine was associated with an im-
munoglobulin A (IgA) sero-response that
was lower than the 2/4/6 months group but
still deemed acceptable (30). Immunization
schedules initiated in newborns were asso-
ciated with a substantially lower frequency
of febrile reactions (0% versus 18%) and a
possible reduction in the small risk of in-
tussusception, which eventually led to the
withdrawal of this vaccine and subsequent
replacement with dif erent attenuated or
human-bovine reassortant rotavirus vac-
Table 1. Recommended immunization schedule for persons aged 0 through 6 years in the United States. Only HBV is given to newborns; thus,
there is a lack of early immunization (orange oval). The window of vulnerability (blue oval) refl ects a phase in which both immune immaturity and
dearth of vaccine protection render the young infant particularly vulnerable to infection. [Adapted from the U.S. Centers for Disease Control and Pre-
vention (CDC) website: http://www.cdc.gov/vaccines/recs/schedules/child-schedule.htm.]
Hepatitis B virus (HBV)
Diphtheria, Tetanus, Pertussis (DTaP)
Haemophilus infuenza type b (Hib)
Pneumococcal conjugate vaccine (PCV)
Inactivated poliovirus (IPV)
Measles, Mumps, Rubella (MMR)
Hepatitis A virus (HAV)
Meningococcal conjugate vaccine (MCV)
Dose 1Dose 2Dose 3Dose 4Dose 5
Yearly seasonal dose
For high risk groups
Lack of early
CREDIT: C. BICKEL/SCIENCE TRANSLATIONAL MEDICINE
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Table 2. Vaccines that have been licensed and/or tested in human newborns and infants. Newborns are from birth to 28 days of age; infants are from 1 month to 2 years old. AS01,
liposomes of MPL (monophosphoryl lipid A) and QS21 (saponin from the tree Quillaja saponaria); AS02, oil-in-water emulsion with MPL and QS21; ID, intradermal; IM, intramuscular; (NANP)50, series of tetrapeptides of four or fi ve Asn-Ala-Asn-Pro repeats of immunodominant B cell epitope of P. falciparum circumsporozoite surface protein; PC, percutaneous;
PRP–OMPC, Hib capsular polysaccharide conjugates with meningococcal outer membrane protein C; PRP–CRM, Hib capsular polysaccharide conjugates with diphtheria toxoid; PRP–T, Hib capsular polysaccharide conjugates with tetanus toxoid; RTS,S/ASO1/2 (GlaxoSmithKline), a pre-erythrocytic vaccine based on P. falciparum circumsporozoite surface protein
and the candidate malaria vaccine in advanced development; SC, subcutaneous; SPf66, synthetic 45-amino acid peptide vaccine containing linked blood and circumsporozoite stage sequences from four diff erent proteins of P. falciparum. *Vaccine package inserts.
Vaccine (series, in
months unless otherwise
Disseminated infection (rare)
CD4, CD8, IFN-γ
Mild, local (1 to10%)
Impaired CD4 and IFN-γ response
Surrogate protection marker
Diphtheria and tetanus
toxoids; pertussis toxin
Mild, local (~10 to 20%)
Hib (2/4 or 2/4/6)
Mild, local (~20 to 40%)
Mild, local (~20%)
for high-risk infants
jugated to diphtheria
toxoid or CRM197
Mild, local (~2 to 40%) to
For Menactra, lower antibody
response when tested at 2/4/6
than in older infants
No serious to mild, local
Infl uenza (6 or 6/8)
Inactivated infl uenza
Mild, local (~10%)
Surrogate protection marker
PTX, pertactin, fHA; or
No serious; mild, local to
higher, systemic (whole)
Suboptimal antibody levels
Diphtheria and tetanus
Lower antibody response at 7
months than those without birth
(21, 22, 25)
Polarizes subsequent TLR
HIV (0/1/3/5), for infants of
Alum-HIV shows less lympho-
proliferation than MF59-HIV
RV (0/2/4 versus 2/4/6)
Four live virus strains
Lower, but still acceptable IgA
levels at birth dose
RTS,S/ASO1/2 (0/1/2 or 7)
(NANP)50 and P. falci-
response than in 1- to 4-year-old
IPV (6/10/14 weeks)
Antibodies to 3
Lower antibody response than IM
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Fractional intradermal IPV. A recent
Cuban study evaluated a reduced dose of
IPV administered at birth with a needle-free
intradermal device (32). T is approach car-
ries great potential for enhanced safety and
ef cacy (33). T e result was inadequate, as
evidenced by suboptimal median polio anti-
body titers, especially in the fractional-dose
arm. However, intradermal vaccination is in
early phases of development and is a poten-
tially important strategy to target immune
responses to draining lymph nodes.
HIV. Vaccine formulations containing
recombinant gp120 derived from HIV-1 ad-
juvanted with either Alum or with MF59—
an oil-in-water emulsion comprising 0.5%
polysorbate 80, 0.5% sorbitan trioleate, and
0.5% squalene—were studied in newborns
of HIV-infected women (34). Infants were
immunized at 0, 1, 3, and 5 months. T e vac-
cines appeared to be safe and well-tolerated
(35) (Table 2). Two immunizations with re-
combinant gp120 proved immunogenic, as
measured by in vitro lymphoproliferative
responses to HIV antigens in more than half
of the immunized children. Although much
work remains to be done in def ning safe
and ef ective HIV vaccines, including those
that may be targeted to newborns, such re-
sults raise the possibility of attempting to
prevent HIV transmission from mother to
child by administering the vaccine shortly
af er perinatal exposure, which is analogous
to postexposure prophylaxis by using mea-
sles, varicella, or hepatitis vaccines.
A GROWING MENU OF ADJUVANTS
T e previous examples illustrate the feasibil-
ity and challenges of neonatal vaccine devel-
opment. In this context, we now ref ect on
recent progress in adjuvant development and
understanding immune ontogeny to project
rational future paths for the development
of neonatal and infant vaccines. Multiple
adjuvant mechanisms have been described
(36–38), including those that create an anti-
gen depot; preserve antigen conformation;
direct antigen to specif c immune cells; acti-
vate antigen-presenting cells; induce mucosal
responses; or induce cytotoxic T cell respons-
es. It should be noted that adjuvants are not
typically approved in and of themselves but
as part of vaccine formulations.
Use of adjuvants that activate antigen-
presenting cells is a particularly ef ective
means of enhancing vaccine ef cacy. How-
ever, in order to reduce reactogenicity, vac-
cine design has increasingly turned to the
use of protein subunit vaccines composed
of single protein molecules that can aggre-
gate to form higher-order structures, poten-
tially at the cost of reduced immunogenic-
ity. In this context, inclusion of adjuvants
in vaccine formulations can be crucial for
antigen-dose sparing, broadening epitopes,
and increasing responses in populations
with distinct immunity, including the very
young. Indeed, expanding awareness of pat-
tern recognition receptors (PRRs) expressed
on leukocytes, including antigen-presenting
cells—as well as other host cells—and their
ligands (microbial and endogenous danger
signals that can act as adjuvants) has opened
a new era in vaccine development (36). To
the extent that the ontogeny of PRR func-
tion has been evaluated, functional expres-
sion has been noted to be age-dependent,
with stimulus-induced expression of T 1-
polarizing cytokines increasing with age
(39); yet, for several families of PRRs this
correlation has yet to be characterized (40).
Another unknown is whether early-life
exposure to adjuvants may contribute to
chronic skewing of an individual’s T 1/T 2
Importantly, TLR agonists are present in
multiple vaccines that have been given to
pediatric populations, including BCG (41)
and the Hib vaccine that was adjuvanted
with a Neisseria meningitidis group B outer
membrane protein, which is a TLR2 agonist
(42). T e connections between this prior ex-
perience with administering TLR agonist-
adjuvanted vaccines to children and current
development of novel vaccine formulations,
in which TLR agonists may be incorporat-
ed as adjuvants, is of en underappreciated.
T ese examples do not, of course, prove that
all TLR agonists are safe and ef ective, but
they do provide proof of concept for using
PRR agonists as neonatal infant vaccine ad-
THE ONTOGENY OF THE INFANT
Newborns possess a distinct innate and
adaptive immune system comprising hu-
moral components, antigen-presenting cells,
and lymphocytes of distinct composition
and function (Fig. 1) (39, 43, 44). Preterm
newborns tend to have even more extreme
dif erences in humoral and cellular immu-
nity compared with those of adults and, cor-
respondingly, an even greater susceptibility
to infection (45) as well as reduced respon-
siveness to subunit glycoconjugate vaccines
(such as pneumococcal conjugate vaccine)
(46). Rational development of neonatal and
infant vaccines will need to take immune
ontogeny into account in preclinical devel-
opment. T e fetal and neonatal immune
systems are biased against T 1 responses,
with CD4 lymphocyte responses that are of-
ten weaker and less sustained than those of
adults. Although B cell antibody responses
(T cell–independent) are impaired during
infancy, T cell–dependent antibody respons-
es mature earlier; nevertheless, multiple im-
munizations might be needed for newborns
and young infants to achieve or sustain
protective titers (44). Indeed, the neonatal
immune system is heavily T 2- and T 17-
biased, presumably to avoid pro-inf amma-
tory/T 1-type allo-immune responses to
maternal tissues that might trigger preterm
birth or spontaneous abortion (39). Birth
triggers a dramatic shif in environment that
challenges the neonatal immune system to
mediate the transition from a sterile intra-
uterine compartment to a foreign antigen–
rich external environment, including initial
microbial colonization of the skin and gas-
T ere are marked dif erences in soluble
immunomodulatory components of new-
born and adult blood plasma (Fig. 1). Sev-
eral mechanisms contribute to skewing
neonatal antigen-presenting cells toward
T 2-type responses—including placenta-
derived mediators, such as transforming
growth factor β, progesterone, and pros-
taglandin E2—that enhance T 2 cytokine
production (47). Transplacental maternal
antibodies can potentially reduce immune
responses, although this ef ect can be over-
come depending on antigen dose and epit-
ope (or epitopes) (48, 49). Relative to adult
blood plasma, neonatal plasma contains
high concentrations of adenosine (Fig. 1),
an endogenous purine metabolite that acts
via adenosine receptors to induce intra-
cellular cyclic adenosine monophosphate
(cAMP) and selectively inhibits production
of T 1-polarizing cytokines (39, 50). New-
born cord-blood also demonstrates lower
plasma concentrations of antimicrobial
proteins and peptides (51) and complement
(45), which play important roles in innate
and adaptive immune responses (52).
Neonatal antigen-presenting cells.
T ere are both quantitative and qualita-
tive dif erences between neonatal and adult
antigen-presenting cells. Newborn cord-
blood monocytes, dendritic cells (DCs), and
monocyte-derived dendritic cells (MoDCs)
demonstrate robust TLR-mediated response
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to support T 17- and T 2-type immunity
[such as interleukin 6 (IL-6) and IL-23],
which promotes defense against extracel-
lular pathogens. However, neonatal mono-
cytes, DCs, and MoDCs exhibit reduced
T 1-type responses [such as tumor necrosis
factor (TNF), interferon-α (IFN-α), and
IFN-γ], including reduced single-cell poly-
functional responses (Fig. 1), which are
important for defense against intracellular
pathogens (53). T is neonatal polarization
might partly ref ect high cytosolic concen-
trations of inhibitory cAMP in newborn
cord-blood mononuclear cells (39). T e
patterns of neonatal cytokine production
appear to be relevant in vivo: During the
f rst week of life, human neonatal peripheral
serum levels of TNF remain low (relative
to human adult serum), whereas levels of
IL-6 increase (54). For many TLR agonists,
cytokine responses increase to adult levels
during the f rst months of life (55). One ap-
parent exception to this pattern is the fam-
ily of TLR8 agonists, which when tested in
vitro induces adult levels of TNF and up-
regulation of co-stimulatory molecules in
newborn and infant whole blood, as well as
cord-blood monocytes and MoDCs (56, 57).
Neonatal lymphocytes. Fetal T cells
are distinct from adult T cells and arise from
dif erent populations of hematopoietic stem
cells present at distinct developmental stages
and biased toward immune tolerance (58).
Neonatal lymphocytes demonstrate a high
proportion of recent thymic
emigrants and have distinct cel-
lular function, including dimin-
ished proliferative and impaired
IFN-γ responses (Fig. 1), the
latter ascribed to promoter hy-
permethylation. Neonatal CD4+
cells show reduced stimulus-
induced CD40 ligand up-regula-
tion and an impaired capacity to
provide help for B cell function.
Moreover, newborns have an in-
creased number and activity of
inhibitory regulatory T cells (Treg
cells) that limit adaptive immune
responses at birth and promote
tolerance (Fig. 1) (59).
T e B cell compartment is
also distinct in early life. Na-
ïve B cells predominate in early
life, whereas CD27+ memory B
cells increase during the f rst 6
months of life (60). Newborns
and young infants use a biased
antibody gene repertoire with a
low frequency of somatic muta-
tions, which might contribute
to poor af nity maturation and
impaired functional antibody
responses (61). Despite these
many limitations, neonatal lym-
phocytes can be activated under
specif c conditions with certain
stimuli (43, 62, 63). For example,
human newborns can mount
CD8+ memory responses during
congenital cytomegalovirus in-
fection (64) and upon BCG im-
munization, as well as antibody
responses to OPV and HBV (19).
Much remains to be learned re-
garding the immunologic and
molecular rules governing ef ective activa-
tion of neonatal and infant immune respons-
es. Overall, rational approaches to the devel-
opment of new vaccines for the very young
must take into account immune ontogeny by
ensuring that vaccine formulations targeting
newborns and infants ef ectively engage their
distinct immune systems.
INTEGRATING IMMUNE ONTOGENY
WITH MODERN VACCINOLOGY
T e present process of vaccine development
for newborns and infants essentially focuses
on ad hoc evaluation of vaccines originally
developed for use in older individuals.
However, the importance of early-life im-
munization is increasingly evident from
Fig. 1. Distinct humoral and cellular components of the neonatal immune system. Neonatal blood plasma
contains a diff erent proportion of key immunomodulatory components than older individuals, including the
presence of maternal antibodies, high concentrations of immunomodulatory adenosine, and reduced concen-
trations of complement, which are important to adaptive immune responses. Diff erences in neonatal leuko-
cytes include impaired migration and reduced Th1-polarizing responses of neonatal APCs to most TLR agonists.
T cell impairments include diminished CD40 ligand expression and reduced IFN-γ production. Neonatal B cells
are predominantly transitional and demonstrate impairments in antibody maturation and affi nity.
CREDIT: C. BICKEL/SCIENCE TRANSLATIONAL MEDICINE
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practical (1), biomedical (63), and economic
(65) perspectives. In this context, the char-
acterization of immune ontogeny in relation
to age-specif c adjuvant ef ects will inform
a new era of targeted vaccine development.
Development of novel vaccine formula-
tions must take into account not only age-
specif c dif erences but also the distinct
immune systems of nonhuman animals,
including mice (66). Accordingly, for pre-
clinical evaluation of pediatric vaccine com-
ponents, including adjuvants, in vitro work
using human neonatal and infant primary
cells in media containing the relevant com-
position of human humoral components
(such as autologous plasma) will be impor-
tant for modeling the distinct immune re-
sponses of neonatal and infant monocytes,
APCs, and lymphocytes (67). Related ap-
proaches have been recently described in
adult settings (68). Results from such in
vitro studies should inform the selection of
appropriate preclinical animal models, to
see whether the adjuvants identif ed in vitro
are bioactive in neonates of the test species.
Clinical trials should ensure that rigorous
biomarker evaluation, including genome-
wide transcriptional and proteomic ap-
proaches, are used to further ref ne age-
specif c markers of safety and ef cacy (69).
T e accelerated schedule approach, in which
trials are designed to extend to earlier ages
of initial immunization, remains impor-
tant. However, if responses to a given vac-
cine formulation administered early in life
are inadequate, then addition of dif erent
adjuvant systems and formulations should
be considered. Studies will need to take into
account not only safety and ef cacy but also
potential vaccine-vaccine interactions that
can lead to interference (70). Optimizing
neonatal and infant vaccine formulations
will also entail evaluation of distinct routes
of administration (71), combination vac-
cines (72), live vector vaccines (73), and the
possibility of genetic immunization (74).
Safety considerations, which are impor-
tant for all biopharmaceutical development,
are especially critical for vaccines because
they are given to healthy individuals. T e
use of these agents in infants places all the
more emphasis on rigorous safety evalua-
tion. Proof-of-concept for safe and ef ective
neonatal immunization exists in the form of
vaccines such as BCG and HBV, which are
given to millions of newborns and which
have good safety prof les. Nevertheless, safe-
ty concerns are paramount in the develop-
ment of any new biologic agent, particularly
ones to be given to healthy newborns and
infants. T e potential benef ts of neonatal
vaccination are thus tempered by appro-
priate social and medical concerns about
safety. Biopharmaceutical development of
neonatal vaccines will have to proceed with
caution within a viable development path-
way, given the urgent unmet needs and great
potential benef ts of early-life immunization
(7, 19). Although animal models will con-
tinue to be important in preclinical develop-
ment, they do not necessarily ref ect human
immunology accurately. Moreover, there are
few if any gold-standard safety biomarkers
with respect to preclinical in vitro studies;
some biomarkers that have been studied in
this context include cytokines, acute-phase
reactants, and prostaglandins (75). It will be
important to benchmark the ability of novel
vaccine formulations to induce respons-
es from human neonatal and infant cells
against existing vaccines in order to develop
an understanding of potential correlates of
protection and reactogenicity.
Correlates of protection are crucial vac-
cine study end-points, including antibody
titers for protection against encapsulated
bacteria and cytotoxic T cell responses for
protection against intracellular pathogens.
In some instances, vaccine formulations
may be approved on the basis of clinical
safety and surrogate markers of ef cacy.
Post-approval phase IV clinical evaluation
can ultimately verify that immune respons-
es known to be protective in adults or older
children are also protective against disease
in neonates and young infants.
ENSURING PROGRESS AND
Although there are several challenges in de-
veloping vaccines for newborns and infants,
proof-of-concept exists that this approach
can be safe and ef ective and represents a
promising strategy to reduce infant mortali-
ty (19). Most vaccine formulations that have
been studied at birth have used Alum as an
adjuvant (Tables 1 and 2); as such, novel
adjuvants that are active at birth might be
key in developing new and more ef ective
neonatal vaccines (40). Progress will require
support for basic and translational research
in neonatal and infant immunology and
vaccinology. Ongoing optimization of prac-
tical regulatory guidelines for vaccine for-
mulation development will also be crucial
to ensuring that safe and ef ective neonatal
vaccines are developed to meet the urgent
global challenge posed by infection.
Given the importance of early-life im-
munization and the vast amounts of new in-
formation regarding adjuvant formulations,
routes of delivery, and immune ontogeny, a
conceptual and practical framework for age-
specif c vaccine development is very much
needed. T e high disease burden early in life
because of respiratory viral infections, in-
cluding respiratory syncitial virus and inf u-
enza, suggests that early-life immunization,
preferably at birth, might be the key to reduc-
ing the burden of these diseases as well. At
particular risk are preterm newborns whose
markedly distinct immune responses render
them at especially high risk of infection (46,
76). National and international regulatory
agencies will need to work with academia
and industry to help def ne and validate spe-
cif c biomarkers for vaccine safety and ef ca-
cy in newborns and young infants. Funding
support from both government sources and
private foundations will be key components
for such progress. In this regard, the recent
coordination by the United States National
Institutes of Health and T e Bill and Me-
linda Gates Foundation to develop and host
a workshop on “Challenges in Infant Immu-
nity” (June 2010; Bethesda, Maryland) was a
welcomed and important development in the
f eld (63). Moreover, international collabora-
tion will be crucial to ensure that formula-
tions, adjuvants, and biomarkers identif ed
apply to diverse populations throughout the
world. Although progress has been made
in reducing infant infection, more than 200
newborns and young infants die each hour
from infection worldwide; therefore, the
challenging but feasible task ahead must be
approached in a thoughtful and prudent yet
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83. Acknowledgments: The authors acknowledge the men-
torship and support of M. Wessels, R. Malley, R. Geha, E.
Guinan, and G. Fleisher. The authors also acknowledge
the advice and support of G. vanden Bossche and C.
Wilson of the Bill & Melinda Gates Foundation. Funding:
O.L. received a Bill & Melinda Gates Foundation Grand
Challenges Explorations Award and is currently funded
by NIH NIAIAD RO1 AI067353-01A1, American Recov-
ery and Reinvestment Act NIH Administrative Supple-
ment 3R01AI067353-05S1, and by Global Health Grant
OPPGH5284 from The Bill & Melinda Gates Foundation.
Competing interests: O.L. has also received reagent
and/or sponsored research support from 3M Drug De-
livery Systems and VentiRx, companies that develop TLR
agonists as immunomodulatory agents. O.L. is named as
an inventor on a patent application for use of certain TLR
agonists as neonatal vaccine adjuvants.
Citation: G. Sanchez-Schmitz, O. Levy, Development of new-
born and infant vaccines. Sci. Transl. Med. 3, 90ps27 (2011).
on July 11, 2011