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Group B streptococcus vaccination in pregnancy: Moving toward a global

maternal immunization program
Flor M. Munoz a,b, , Patricia Ferrieri c,d

Department of Pediatrics, Section of Infectious Diseases, Baylor College of Medicine, One Baylor Plaza, BCM-280, Houston, TX 77030, United States
Department of Molecular Virology and Microbiology, Baylor College of Medicine, One Baylor Plaza, BCM-280, Houston, TX 77030, United States
Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Mayo MC-134, 420 Delaware St. SE, Minneapolis, MN 55055, United States
Department of Pediatrics, University of Minnesota Medical School, Mayo MC-134, 420 Delaware St. SE, Minneapolis, MN 55055, United States

a r t i c l e

i n f o

Article history:
Available online xxx
Group B streptococcus
Maternal immunization
Global program

a b s t r a c t
A group B streptococcus vaccine for pregnant women would add to the currently available vaccines given
during pregnancy to protect mothers and their infants against serious and potentially lethal diseases,
including tetanus, inuenza, pertussis and meningococcal infection. Implementation of the administration of these high priority vaccines during routine prenatal care would result in a maternal immunization
program with the potential to have a positive impact in public health globally, by reducing maternal and
neonatal morbidity and mortality.
2012 Elsevier Ltd. All rights reserved.

1. Introduction
Immunizing pregnant women with a safe and effective vaccine
has been shown to protect both the mother and her infant against
serious and potentially lethal infectious diseases. The impact of this
strategy as a public health intervention has been documented with
the implementation of the World Health Organizations (WHO)
maternal-neonatal tetanus elimination program worldwide. However, the potential impact of maternal immunization in public
health is much greater when we consider it offers the opportunity
to protect pregnant mothers and their infants against infections
that are especially relevant during pregnancy and in the neonatal
period and for which there might be limited or inadequate alternative methods of prevention.
The concept of maternal immunization is simple: vaccinated
pregnant women boost existing levels of circulating antibodies that
can then be transferred transplacentally to the fetus by an active

Abbreviations: GBS, Group B streptococcus; WHO, World Health Organization;

ACIP, Advisory Committee on Immunization Practices; CDC, Centers for Disease Control and Prevention; ACOG, American College of Obstetrics and Gynecology; GACVS,
Global Advisory Committee on Vaccine Safety; MNT, Maternal-Neonatal Tetanus;
AAP, American Academy of Pediatrics; AAFP, American Academy of Family Practice;
EPI, Extended Program on Immunization; GAVI, Global Alliance for Vaccines and
Corresponding author at: Department of Molecular Virology and Microbiology,
Baylor College of Medicine, One Baylor Plaza, Suite 221-D, BCM-280, Houston, TX
77030, United States. Tel.: +1 713 798 5248; fax: +1 713 798 6802.
E-mail address: (F.M. Munoz).

transfer process that begins in the second trimester of gestation

and continues until the day of delivery. It is through this mechanism that mothers naturally endow infants with sufcient levels of
IgG antibodies to be protected against numerous pathogens in the
rst months of life while the infants immune system matures.
Immunizing women during pregnancy has distinct advantages
from both individual and public health perspectives. Pregnant
women have good immune responses to vaccines and are likely to
be healthy and benet from the immunity achieved through vaccination. Maternal immunization provides protection of mother,
fetus, and infant with one vaccine, one intervention. Pregnant
women are accessible to receive vaccinations during routine prenatal care. Protecting mothers from infection has the potential
to have a benecial effect on the occurrence of fetal loss, stillbirth, prematurity, and other infant outcomes such as low birth
weight and risk for infection after birth. In addition to the actively
transported transplacental antibodies, breast milk antibodies may
protect infants in the rst few months of life. Healthier mothers
and infants require fewer medical interventions, including the use
of antibiotics, and lower cost of care during pregnancy and after
delivery. Maternal immunization, added to routine childhood and
adolescent vaccination schedules, strengthens public health programs with a common goal: to promote and ensure maternal and
child health.
2. Recommended vaccines in pregnancy US and worldwide
In the United States, the Advisory Committee on Immunization
Practices (ACIP) of the Centers for Disease Control and Prevention

0264-410X/$ see front matter 2012 Elsevier Ltd. All rights reserved.

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(CDC), and the American College of Obstetrics and Gynecology

(ACOG), recommend that women receive vaccinations during pregnancy when a disease poses a signicant risk to the mother or
the baby, and there is a safe and effective vaccine available that
is unlikely to cause harm [1,2]. Based on risk vs. benet considerations, women can routinely receive tetanus toxoid (usually in
the form of tetanus toxoid alone or in combination with diphtheria toxoid), inactivated trivalent inuenza vaccine, and more
recently, the adult formulation of acellular pertussis vaccine in
combination with tetanus and diphtheria toxoids (Tdap) [3,4].
Other vaccines that may be administered to pregnant women in
circumstances when women might be at increased risk due to the
presence of underlying conditions, occupational exposure, exposure during outbreaks, or travel include Hepatitis A and B vaccines,
meningococcal and pneumococcal vaccines, polio and even yellow
fever vaccines. In general, live vaccines such as varicella, measles,
mumps, rubella, and live inuenza vaccines are contraindicated in
pregnancy because of concerns for the theoretical risk of fetal infection with the vaccine attenuated live virus. However, in instances
where these vaccines have been given inadvertently to women who
were pregnant, no clinical infection or other adverse outcomes
have been documented. In the immediate post-partum period,
women can receive all vaccines, particularly rubella, inuenza vaccines, and Tdap. Worldwide, the WHO recommends vaccination
of pregnant women with tetanus toxoid (alone or in combination
with diphtheria toxoid or pertussis antigens), inactivated trivalent
inuenza vaccine, and in certain high risk areas or endemic regions,
meningococcal type A vaccine [57]. During the 26th annual meeting of the Global Advisory Committee on Vaccine Safety (GACVS)
in Geneva, Switzerland in June 2012, the committee reviewed the
topic of safety of vaccines during pregnancy and lactation. The
committee recognized the availability of vaccines that have the
potential to reduce maternal and fetal morbidity and mortality
from preventable infectious diseases, and suggested that optimal
protection against diseases that pose a higher risk in pregnant
women and their offspring should be balanced against the risk
of adverse outcomes that theoretically could affect the fetus as a
result of vaccination in pregnancy. The GACVS established a subgroup to review the safety prole of several important vaccines
for pregnant and lactating women, including inuenza vaccine
and rubella-containing vaccines given inadvertently to pregnant
women. The GACVS concluded that the data remain very reassuring for the use of vaccines during pregnancy, with no evidence of
fetal outcomes identied. Furthermore, the committee stated that
Protection of mothers at risk and their young infants will be critical
to attain the reduction of morbidity and mortality due to infections
that affect many populations around the world [8].
2.1. Tetanus toxoid vaccine
Maternal tetanus infection occurs due to contamination during unclean deliveries or abortions, while neonatal tetanus results
from Clostridium tetani infection of the umbilical cord cut with
contaminated scissors or covered with unclean materials. When
appropriate supportive care is not available, the mortality of
tetanus is practically 100% in newborns. Natural infection does
not result in long term protection against tetanus; immunity can
only be achieved though active immunization or acquired passively from mother to infant during pregnancy. Immunity from
immunization wanes and repeated booster doses of tetanus toxoid containing vaccines are required throughout life to maintain
adequate protective levels of at least 0.10.2 IU/ml as measured
by standard ELISA essays. Tetanus toxoid vaccines that are safe
and effective have been used since the 1940s, resulting in a
signicant reduction of tetanus mortality where childhood and
adult immunization schedules, that include routine tetanus toxoid

immunization, were implemented. A landmark study in Papua New

Guinea in 1961 demonstrated the efcacy of maternal immunization with tetanus toxoid in the prevention of neonatal tetanus and
reduction of neonatal mortality [9].
In many countries worldwide, vaccination against tetanus is
routinely offered to pregnant women, usually during prenatal care
contacts, as part of the WHO Maternal-Neonatal Tetanus (MNT)
elimination program [10]. For women who have never received
tetanus vaccine, or have no documentation of such immunization, a total of ve doses is recommended: two doses given one
month apart in the rst pregnancy (known as TT2), then one dose
in each subsequent pregnancy (or intervals of at least 1 year), to
a total of ve doses. The rationale for this intervention is that
repeated doses are necessary to achieve long lasting protection.
In areas where immunization fails to reach a substantial proportion of pregnant women and mortality from neonatal tetanus
remains prevalent, the high-risk approach is suggested. In addition to vaccinating pregnant women, all women of child-bearing
age (usually between 15 and 45 years of age) living in high risk
districts are targeted with three properly spaced doses of tetanus
toxoid (given over a 12-month period) through specially organized
supplementary immunization activities. This approach focuses on
providing tetanus vaccination in areas where women have limited
or no access to routine vaccination. High risk areas are identied by systematic analysis of routinely reported district data and
local knowledge. The other components of the elimination program include clean deliveries (deliveries in health facilities and/or
assisted by medically trained attendants) to reduce effectively MNT
and other causes of maternal and neonatal mortality, and local
surveillance for neonatal tetanus mortality.
Despite underreporting due to incomplete implementation of
surveillance systems for neonatal tetanus in many developing
countries, the success of the MNT elimination program has been
documented throughout the world. The WHO estimates that in
2008 (the latest year for which estimates are available), 59,000
newborns died from neonatal tetanus, which represents a 92%
reduction from twenty years prior in the late 1980s when WHO
estimated that 787,000 newborns died of neonatal tetanus and
the estimated annual global neonatal tetanus mortality rate was
approximately 6.7 neonatal tetanus deaths per 1000 live births. In
some developing countries, tetanus was responsible for up to one
third of all neonatal deaths. In 1989, the 42nd World Health Assembly called for the global elimination of neonatal tetanus. In 1990,
the World Summit for Children listed neonatal tetanus elimination
as one of its goals. While progress continues, reaching the goal of
elimination has proven to be challenging. The deadline for elimination has been revised on several occasions and by February 2012,
34 countries have not yet reached MNT elimination status, dened
as having <1 case per 1000 live births. Activities to achieve this goal
are ongoing in these countries.
Countries working toward the elimination of MNT are encouraged to develop a plan of action, detailing how they would proceed
to eliminate MNT through the implementation of the WHO recommended strategies. The plan of action is then submitted to UNICEF
or other partners for nancial and technical support. One major
component of most plans is the implementation of tetanus supplementary immunization activities in high risk districts. These
activities are then implemented as per the countrys capacity and
available resources. The criteria to label districts as high risk
are country-specic. In practice, three rounds of campaigns are
organized in the selected areas with at least one month interval
between rounds 1 and 2, and at least six months between rounds
2 and 3. Tetanus vaccination through supplementary immunization activities provides protection for at least 5 years for those who
receive all three doses of vaccine, but needs to be complemented
by follow-up doses, usually given as part of routine antenatal care.

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In many countries, tetanus supplementary immunization activities

are implemented in a phased manner, therefore, it can take several
years before all high risk districts are targeted. Missed opportunities for vaccination during pregnancy are reasons for inadequate
coverage of pregnant women. Furthermore, when women do not
receive prenatal care until late in pregnancy, receipt of tetanus vaccine does not result in optimal immunity for the mother or the
infant. Therefore one common challenge to overcome is educating
pregnant women and providing opportunities to receive prenatal
care earlier in pregnancy. Not offering vaccination to post-partum
women is also a missed opportunity. Sensitivity to local cultural
beliefs and the sociopolitical environment is important to promote
prenatal care and immunization. Once MNT elimination has been
achieved, maintaining elimination requires continued strengthening of routine immunization activities for both pregnant women
and children, maintaining and increasing access to clean deliveries,
and reliable neonatal tetanus surveillance.
2.2. Inuenza vaccine
Pregnant women have a high risk of complications and death
from inuenza, even in the absence of underlying medical conditions, particularly during the second and third trimesters of
gestation. Reported since the 1918 Spanish inuenza pandemic,
this increased risk has been observed in interpandemic seasonal
inuenza epidemics, and was most notable during the recent 2009
H1N1 inuenza A pandemic [1118]. In 2009, pregnant women
were at high risk to be hospitalized, admitted to the intensive
care unit, require mechanical ventilation, and die from inuenza,
particularly if they were in their 3rd trimester of gestation or
had an underlying condition, such as asthma. Five percent of all
reported 2009 H1N1 inuenza deaths in the U.S. were pregnant
women, while only approximately 1% of the population was estimated to be pregnant. The median age of mothers who died was 25
years (range 1443 years). Severe illness in the post-partum period
and an increased rate of premature birth (30.2%) were also documented [19,20]. In addition to prematurity, miscarriages, stillbirth
and emergency Cesarean sections were reported in women infected
with H1N1 pandemic inuenza A [21].
Inactivated inuenza vaccine is recommended in the United
States for women who will be pregnant during inuenza season. Inuenza vaccine has been given to pregnant women
since the 1950s. Initially, the vaccine was recommended for
pregnant women who had other underlying medical conditions
that increased their risk for complications from inuenza, however, in 1997 it was recommended for routine administration to all
pregnant women in the 2nd and 3rd trimesters of gestation, and in
2004 the recommendation was changed to allow vaccination for
all pregnant women in any trimester. Importantly, post-partum
vaccination is also recommended during the inuenza season if
women are not vaccinated during pregnancy (cocoon strategy to
also protect infants), and breastfeeding is not a contraindication to
vaccination. These recommendations are supported by the American Academy of Pediatrics (AAP) and of Family Practice (AAFP), and
by the American College of Obstetrics and Gynecology (ACOG), who
consider inuenza vaccination as an essential element of prenatal
care [22]. In 2005, the WHO adopted these recommendations given
the potential benet of inuenza vaccination for women worldwide
[23]. In 2009, based on available safety data and the substantially
elevated risk for a severe outcome in pregnant women infected with
the pandemic virus, SAGE recommended that any licensed vaccine
can be used in pregnant women, provided no specic contraindication has been identied by the regulatory authority [24].
However, only approximately 13% of pregnant women reportedly used to receive inuenza vaccine in the US every year. That
is, until the 2009 H1N1 pandemic when the impact of inuenza

in pregnant women and in the outcome of their pregnancies was

salient, resulting in close to 50% coverage that year and in subsequent seasons. One of the most important consequences of the
2009 H1N1 pandemic was the renewed interest on maternal immunization and the proliferation of clinical studies, which continue
to contribute to the existing body of evidence on the safety and
benets of inuenza vaccine for pregnant women.
Further support for inuenza vaccination during pregnancy was
provided by a pivotal study in Dhaka, Bangladesh, that demonstrated the benets of inuenza vaccine for infants of vaccinated
mothers. In this trial, 340 pregnant women received inactivated
inuenza or pneumococcal vaccine in the 3rd trimester of gestation. Mothers who received inuenza vaccine were signicantly
less likely to have respiratory illness with fever (36% reduction),
and clinic visits (25% reduction), while infants of vaccinated mothers had a 29% reduction in respiratory illnesses with fever, and 42%
reduction in clinic visits. The effectiveness of the vaccine against
laboratory conrmed inuenza in infants up to 6 months of age was
63% (95% CI 585) [25]. Similar results were reported in a study
among 1160 Navajo and White Mountain Apache Indian mother
infant pairs in the US, where a 41% reduction in the risk of laboratory conrmed inuenza virus infection and a 39% reduction in the
risk of hospitalization for inuenza-like illness was documented in
infants born to mothers who received inuenza vaccine, compared
with infants born to unvaccinated mothers over 3 inuenza seasons
from 2002 to 2005 [26].
Documentation of the benet and safety of the vaccine for
mothers and infants as well as continuing surveillance of disease and adverse events have been instrumental in improving the
acceptance of inuenza vaccine in pregnant women. Barriers to
immunization are, for the most part, related to concerns for potential side effects, belief in the efcacy of the vaccine, and often
logistical implementation issues. Recommendation of vaccination
by obstetric providers and education of women and health care
providers on the benets of inuenza vaccine are also fundamental
to improve coverage.
2.3. Meningococcal vaccine
Neisseria meningitidis is the leading cause of meningitis and fulminant sepsis in many countries. In some highly endemic regions,
meningococcal disease is a signicant public health issue. The
highest annual incidence of meningococcal disease in the world,
reaching up to 1000 cases per 100,000 persons during epidemics,
is reported in the African meningitis belt, the area in sub-Saharan
Africa extending from Senegal to Ethiopia [7]. Serogroups A, C, and
W135 and a newly recognized group X have caused epidemics, but
serogroup A is the most prevalent. In countries where Haemophilus
inuenzae type b and pneumococcal vaccines are routinely given
to children, meningococcal meningitis is the most common type
of bacterial meningitis, particularly in infants and adolescents.
In addition to living or traveling to highly endemic regions, risk
factors for meningococcal disease have been identied, including
crowding, tobacco smoke, anatomic or functional asplenia and deciencies in the complement system [7].
Nasopharyngeal colonization and natural infection result in
serum bactericidal antibodies, the correlate of protection for
meningococcal disease. Newborns receive IgG antibodies at birth,
with protection depending on factors such as maternal levels at
the time of delivery and gestational age at birth. Polysaccharide
and conjugate vaccines, which elicit immunological memory, are
effective in the protection against meningococcal disease caused
by serogroups A, C, Y, and W-135. A safe and effective serogroup A
conjugate meningococcal vaccine is available for use in the African
meningitis belt for persons 129 years of age. Given the high risk of
disease in the region, the WHO has recommended that serogroup A

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conjugate vaccine, as it is introduced in routine immunization programs and vaccine campaigns in several African countries, should
be administered also to women who are pregnant or lactating [27].
2.4. Pertussis vaccine
Despite routine childhood vaccination, pertussis continues to
cause morbidity and mortality in industrialized countries, and to
be a signicant public health problem worldwide [28]. Infants who
are not vaccinated or who are too young to be vaccinated (<2
months of age) have the highest burden of morbidity and mortality. Immunity from childhood vaccination wanes in women of
childbearing age so that infants receive little to no transplacentally transmitted antibody and are susceptible from the time of
birth until they receive their primary series of pertussis containing
vaccines [29]. Whole cell pertussis vaccine, in combination with
tetanus and diphtheria toxoids given to infants since the 1940s in
the US, and part of the WHOs Extended Program on Immunization (EPI) since 1974, resulted in a signicant reduction (>90%) of
pertussis. However, a resurgence of pertussis disease and cyclic
epidemics continue to occur with increasing frequency since the
1980s, resulting in the need to modify immunization schedules.
This now includes a pre-adolescent and an adult booster of tetanus
toxoid and reduced concentration of diphtheria toxoid and acellular pertussis antigens vaccine (Tdap) to provide immunity to those
who are considered the reservoir and main source of pertussis, thus
decreasing transmission to newborns and young infants. Particular attention is given to families with a newborn, recommending
post-partum vaccination of the mother, and vaccination of fathers
and all family members to indirectly protect the infant (cocooning)
Despite these interventions, albeit imperfectly implemented,
infant mortality from pertussis continues to increase. In 2011,
the ACIP recommended that Tdap vaccine should be given to
pregnant women in their second or third trimester of gestation
if they have not received Tdap vaccine before in order to boost
maternal antibodies and provide passive protection to the infant
in those critical rst two months of life [31]. The recommendation is based on the considerations of minimal risk of maternal
immunization vs. anticipated signicant benet for the infant, and
it is supported by ACOG and the AAP [32]. The levels of antibody necessary to protect the infant are not known. However,
women who receive whole cell or acellular pertussis vaccines during pregnancy have documented increases in the concentration
of antibodies to vaccine antigens with no safety concerns [33,34].
Furthermore, infants born to women who received a whole cell
pertussis vaccine during pregnancy were protected from clinical
pertussis [33]. Studies of maternal immunization with Tdap are
ongoing to evaluate transplacental transmission, duration of passively transmitted antibodies, and effect of maternal immunization
on infant responses to active DTaP vaccination. Surveillance of pertussis disease and vaccine adverse events in women immunized
during pregnancy are established in the US.
3. Potential impact of GBS maternal immunization:
understanding the epidemiology and burden of disease in
pregnant women and their infants
Group B streptococcus (GBS) is the most frequent cause of
neonatal sepsis in the United States. The implementation of routine screening for GBS for pregnant women in the third trimester of
gestation and administration of intrapartum antibiotic prophylaxis
in women who are colonized has resulted in a dramatic drop in the
incidence of early onset neonatal sepsis associated with GBS. However rates have now reached a plateau at 0.34 cases per 1000 live

births [35]. Furthermore, this intervention has not had any effect on
the incidence of late onset neonatal sepsis caused by GBS, estimated
to be also around 0.35 per 1000 live births. Similarly, a high incidence of GBS neonatal sepsis has been described in other regions
of the world [3638]. However, there is considerable variation in
the reported incidence of neonatal Group B streptococcal disease
in developing countries, ranging from 0 to 3.06 per 1000 live births
[39]. GBS is considered a predominant cause of neonatal sepsis in
southern Africa and Kenya, but the reported incidence in Asia is
lower [39].
The mechanism of acquisition of GBS is mother to infant transmission in the peripartum period or horizontal transmission in the
neonatal period. The onset of infection shortly after birth does not
allow for infant immunization as a method of prevention. Maternal
intrapartum antibiotic prophylaxis has no effect on late onset GSB
infection in the newborn. Experimental vaccines for one of the most
common serotypes, GBS type III, have been evaluated in phase III
trials in pregnant women, demonstrating they were safe and well
tolerated, and resulted in a substantial antibody response and signicantly higher antibody levels in infants at the time of birth and
in the rst few weeks of life compared to controls [40,41]. Vaccines
to protect mothers and infants against multiple prevalent serotypes
have the potential to reduce the morbidity and mortality caused by
GBS in the neonatal period.
The development of a program of GBS maternal immunization provides the opportunity to gain a better understanding of
the epidemiology and burden of GBS disease in pregnant women
and their infants in different geographic regions and patient populations. Drawing from the experience with vaccines currently
recommended in pregnancy, in order to develop the most appropriate vaccine and design research and implementation protocols,
it is critical to know the local background rates of GBS colonization
and disease in mothers and infants, GBS associated morbidity and
mortality rates, and serotype prevalence, with special attention to
invasive isolates. Obtaining this information may be particularly
challenging in developing countries, where the rst action should
be the implementation of prospective population-based surveillance studies to have a clear understanding of the burden and
impact of GBS disease in the region. The expert panel recognized
the need to select representative countries where establishing
solid collaborations for research and capacity building are feasible.
Capacity building is a key element for the success of the program
over time. The panel suggested working with local collaborating
centers and using existing models of research partnership based
on active local involvement at different levels and adequate training of local personnel, in order to produce high quality research
studies. Collaboration with national and local authorities as well as
international organizations such as the WHO, the Gates Foundation,
the GAVI Alliance, and others, as well as academia is highly encouraged in this phase. Overall, the goal would be to develop regional
reference centers to collect data with applicability to several neighboring countries, and raise awareness of the disease among the
population and local authorities. Ongoing surveillance would allow
the documentation of objective effects after the implementation of
vaccination, specically in perinatal and neonatal morbidity and
mortality (overall and associated with GBS), and other specic
outcomes such as neonatal sepsis, prematurity, and perinatal complications.

4. Research opportunities
The development of a GBS maternal immunization program
provides the opportunity to advance the current knowledge of
GBS infection and disease in pregnant women and newborns.
When dening the epidemiology of the disease, the expert panel

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suggested the use of technology that allows simplicity in sample

collection and shipment, and analysis in a central laboratory with
the capability to process submitted specimens. Multiplex PCR for
detection of colonization may be a starting point that can then be
expanded to study disease burden and later on impact of vaccination.
The working group suggested several areas of research that
deserve consideration when evaluating a GBS vaccine and
implementing a maternal immunization program. The safety,
immunogenicity and efcacy of the vaccine should be established in
clinical trials prior to the implementation of the program. Immunologic correlates of protection should be determined, particularly for
late onset disease. It is important to understand how the vaccine
works in pregnant women: for example, can T-cell responses be
elicited with vaccination? Is the antibody response to the vaccine
different in women who are or were previously colonized with GBS
compared to GBS nave women? Does boosting occur in those previously exposed or vaccinated? It would be interesting to learn more
about the functionality of antibodies to GBS, including their avidity,
afnity and opsonophagocytic killing, and to understand antibody
subtype and isotype distribution, vaginal antibodies and their effect
on vaginal GBS colonization. Also important is learning about the
production and transfer of breast milk antibodies and the protection they may provide. Lastly, determining the duration of serum
antibodies and of the protection they confer in mothers and infants
is necessary to assess the need for repeated vaccination of mothers in subsequent pregnancies. In addition to following the impact
of vaccination in the incidence of early and late onset GBS disease,
follow up studies should assess the effect of maternal vaccination
on infant response to natural infection with GBS.

6. Surveillance, monitoring and reporting of adverse events

During the conduct of clinical studies and after the licensure
of a GBS vaccine for maternal immunization, it is necessary to
establish methods to ensure continued surveillance of the disease
burden and mortality in both mothers and infants, monitoring and
reporting adverse events in pregnant women following the use of
vaccine, and documenting any potential adverse events to the fetus
and newborn after maternal immunization. A mechanism for reporting of these events must be in place and accessible to health care
providers and the public in general. Regular assessment of reports
and evaluation of events by qualied authorities, followed by disclosure of results to the public will result in greater condence in
the safety of GBS vaccine in pregnant women.
7. Education and collaboration
Moving toward a GBS maternal immunization program requires
signicant effort to educate the public and providers on the safety
and benets of the vaccine. During the implementation period and
after, it is important to target groups with the highest likelihood to
benet from vaccination but also those who have misconceptions
or mistrust the vaccine and/or the health care system. Information should be made readily available and disclosed transparently.
Collaboration with support groups, parent organizations and the
media could be benecial when introducing the program. Similarly,
maintaining close collaboration between international professional
organizations, physicians, scientists, and regulatory authorities to
evaluate the use and safety of GBS vaccines in pregnant women
over time should be a priority.
8. Conclusions

5. Regulatory considerations
The implementation of a GBS maternal immunization program
requires a thorough understanding of the importance of GBS in
the region and compliance with local and international regulatory
requirements. Firstly, prevention of GBS maternal and neonatal disease and mortality must be considered a public health priority. It is
critical for investigators and groups supporting the implementation
of maternal GBS vaccination to understand local regulations and
challenges when introducing a new vaccine. The selection of the
target population for immunization should be based on solid local
epidemiology and risk assessment. Sensitivity to cultural beliefs
and practices, as well as political inuences must be taken into
consideration. Economical factors, such as the cost of the vaccine
and the operational costs of vaccination, and logistics of the distribution of the vaccine (one dose and single dose vial are easier to
implement than multiple doses), product stability, and cold chain
requirements, impact the accessibility of the vaccine and implementation of the vaccination program.
The WHO has published the requirements for vaccines intended
for use in large-scale public health interventions [42]. The vaccine must be safe and have a signicant impact against the disease
it prevents in all target populations; the vaccine must be easily
adapted to current immunization schedules and timing of other
national immunization programs (this is particularly relevant for
vaccines intended for infants and young children, however it may
be applicable to new vaccines introduced to established prenatal
care programs); the vaccine must not interfere with the immune
response to other vaccines given simultaneously (which poses the
question about co-administration of GBS conjugate vaccine and
tetanus toxoid vaccines); it must be formulated to meet common
technical limitations such as refrigeration and storage capacity, and
be appropriately priced for the economy where it is to be implemented.

A group B streptococcal vaccine for maternal immunization has

the potential to provide equity in prevention of GBS disease in
mothers and newborns when compared to intrapartum antibiotic
prophylaxis, which may not be uniformly utilized, or the current
standard of care which may be no preventive interventions in many
countries around the world. A GBS vaccine for pregnant women
adds to the currently available vaccines that can be given during pregnancy to protect mothers and their infants against serious
and potentially lethal diseases including tetanus, inuenza, pertussis and meningococcal infection. Successful introduction of these
vaccines during routine prenatal care will result in a maternal
immunization program with the potential to have a positive impact
in public health globally, by reducing maternal and neonatal morbidity and mortality.
Conict of interest statement
The authors have no conicts of interest to declare.
The authors acknowledge the contributions of the members
of this working group, participants in the meeting sponsored by
Novartis Vaccines held in Siena, Italy, in July 2012: Oretta Finco,
Maria Rosaria Romano, Kwasi Amfo, Fabio Bagnoli, Phil Boucher,
Ennio de Gregorio, Giuseppe Del Guidice, Paul Heath, Joachim Hombach, Dominika Kovack, Calman MacLennan, Lucia Marconcini,
Graziella Oreci, Mark Steinhoff, and Daniela Stranges.
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immunization program. Vaccine (2012),