THEMATIC REVIEW SERIES ON VACCINES

Routine Childhood Vaccines Given in the

First 11 Months of Life
Robert M. Jacobson, MD

Abstract

The US Advisory Committee on Immunization Practices recommends that infants beginning at birth
receive several vaccines directed against a variety of infectious diseases that currently pose threats of
morbidity and mortality to infants and those around them, including the 3-dose hepatitis B (HepB)
series. The first dose is due at birth. This series protects against maternal-infant transmission of the
HepB virus and against exposure the rest of the infant’s life. At age 2 months infants are to receive not
only their second dose of HepB vaccine but also a series of vaccines directed against diphtheria,
tetanus, pertussis, pneumococcus, rotavirus, poliovirus, and Haemophilus influenzae type b. At 4
months, infants are to repeat those vaccines except for the HepB vaccine. At age 6 months infants are
to finish the HepB series and receive the third doses of the other vaccines received at 2 and 4 months
except for the rotavirus vaccine, depending on the brand used. Also, starting at 6 months, depending
on the time of year, infants are to begin a 2-dose series against influenza separated by 28 days. Each of
these vaccines is due at a time when the vaccine works to protect against an immediate risk and to
provide long-term protection. These vaccine-preventable diseases vary in terms of the nature of
exposure, the form of the morbidity, the risk of mortality, and the ability of routine vaccination to
prevent or ameliorate harm.
ª 2019 Mayo Foundation for Medical Education and Research n Mayo Clin Proc. 2020;95(2):395-405

P
ublic health officials in the United
States identified routine childhood
immunizations as one of the most
important public health achievements of
the 20th century and again in the first
decade of the 21st century.1-3 Throughout
that time and even since, the routine child-
hood immunization schedule has evolved,
with new additions of vaccines to that
schedule as well as important revisions to
the timing and dosing of well-established
routine childhood immunizations.4 This the-
matic review surveys those routine child im-
munizations given in the first 11 months
after birth (Figure).4 Although the World
Health Organization has adopted interna-
tional standards for routine childhood im-
munization,5 the framework presented
herein reflects routine childhood immuniza-
tion as recommended by the US Advisory
Committee on Immunization Practices
(ACIP),4,6 and the data regarding those rec-
ommendations reflect US epidemiology.7,8
For each routine child immunization, this
review examines what the ACIP recom-
mends, why the ACIP recommends what it
recommends, what that immunization has From the Department of
Pediatric and Adolescent
accomplished, where recent developments Medicine and Department
have occurred, and what still needs to be of Health Sciences
done. Research, Mayo Clinic,
Rochester, MN.
HEPATITIS B
Hepatitis B (HepB) infection can cause an
acute liver inflammation marked by prodro-
mal malaise, fever, nausea, anorexia, abdom-
inal pain, and arthralgia, followed by
jaundice, liver tenderness, liver swelling,
and acholic stools.7 Rarely, fulminant infec-
tions can occur, leading to death or liver fail-
ure requiring liver transplant. Half of all
individuals acutely infected have no symp-
toms. Although most of those acutely
infected clear the infection and develop im-
munity for life, the infection can persist for
decades, leading to cirrhosis and hepatocel-
lular carcinoma. Currently, in the United
States, approximately 1 or 2 million people
have chronic infection with HepB, with

Mayo Clin Proc. n February 2020;95(2):395-405 n https://doi.org/10.1016/j.mayocp.2019.06.007 395

www.mayoclinicproceedings.org n ª 2019 Mayo Foundation for Medical Education and Research

7000 new cases of chronic infection per
year.7,9 A quarter of those with chronic
infection develop either cirrhosis or liver
cancer, from which 4000 people die every
year in the United States.7 The infection
passes at the time of parturition from mother
to child. This form of transmission results in
possibly as many as 1000 infant infections
per year in the United States despite the cur-
rent recommendations for universal infant
immunization.9 The infection also spreads
by exposure to blood or semen. High-risk
groups include those who abuse injecting
drugs, those who are promiscuous, men
who have sex with men, health care workers,
young people with diabetes, and those un-
dergoing dialysis.
Infants and children are at high risk for
chronic infection. Approximately 85% of in-
fants infected at birth will go on to develop
chronic infection.7,9 Young children who
are infected have a 30% chance of developing
chronic infection, whereas older children
and adults have a 5% risk of not clearing
the infection.7
Current recommendations call for all in-
fants to undergo immunization against
HepB, starting the series on the day of birth
(Figure).4,9 Initiating the 3-dose vaccine se-
ries at birth and completing the series in 6
months’ time substantially minimizes the
risk that the infant will acquire the infection
from the mother. Coupling the 3-dose series
with the administration of passive immunity
in the form of HepB immunoglobulin further
reduces the risk. The ACIP recommends this
combination for infants whose mothers
demonstrate infection through prenatal
screening and for those with birth weights
less than 2000 g born to mothers who were
not screened during pregnancy. Those with
birth weights less than 2000 g are less likely
to respond to the first dose of HepB vaccine.
The vaccine is a recombinant vaccine
generated by using laboratory-altered yeast
carrying the protein-manufacturing DNA
for the HepB surface antigen. The
manufacturing process takes proteins gener-
ated from growth in cultured yeast and
purifies them. Three manufacturers are
n n
396 Mayo Clin Proc.
MAYO CLINIC PROCEEDINGS
licensed in the United States to make the
HepB vaccine: GlaxoSmithKline, Merck &
Co, and Dynavax Technologies Corp. The
first 2 manufacture vaccines licensed for
use in all ages.9,10 The third manufactures
a form of the vaccine with a novel adjuvant
that is licensed only for adults.10
Universal vaccination against HepB in
children began in 1991.11,12 In 2017 in the
United States, 91.4% of children 19 to 35
months of age had completed the 3-dose se-
ries and 73.6% received their first dose as a
birth dose.13 The rate of acute HepB infec-
tion in children 1 to 9 years of age fell 80%
from a prevaccination rate of 0.8 per
100,000 in 1991 to 0.1 per 100,000 in
2000.11 Universal vaccination of infants
against HepB has overcome the failure of
risk-based vaccination and has reduced the
number of chronic hepatitis infections in
populations at risk.11
Recent developments include the addi-
tion of screening for HepB DNA in addition
to screening for HepB surface antigen in
mothers-to-be prenatally if those mothers
test positive for HepB surface antigens.9
Those mothers then can receive treatment
to reduce their infectivity as well as their
complications from HepB infection. Further-
more, recent changes made in 2018 to the
universal recommendations for vaccination
of infants call for no grace in permitting
low-risk babies to wait until 1 month of
age for their first doses of HepB vaccine.
Updated modeling estimates that we still
have nearly 1000 babies born in the United
States each year who develop HepB infec-
tion.14 Experts anticipate that the new revi-
sions to prenatal screening and the birth
dose will reduce this rate, but part of the
problem remains the lack of prenatal
screening combined with increased rates of
home birth with families resistant to univer-
sal vaccination at birth.15,16 Medical care and
public health organizations need to better
communicate their strong recommendations
for prenatal screening as well as for universal
HepB vaccination and build systems for pro-
vider prompts and fail-safes to ensure testing
and immunization.
February 2020;95(2):395-405 https://doi.org/10.1016/j.mayocp.2019.06.007
www.mayoclinicproceedings.org
ROUTINE CHILDHOOD VACCINES

Vaccine Birth 1 mo 2 mo 4 mo 6 mo 9 mo 12 mo 15 mo 18 mo 19-23 mo 2-3 y 7-10 y 13-15 y 17-18 y

4-6 y 11-12 y 16 y

Hepatitis B Dose 1 Dose 2 Dose 3

Rotavirus 1 (2-dose See

Dose 1 Dose 2
series); rotavirus 5 (3-dose series) notes

Diphtheria, tetanus, and acellular

Dose 1 Dose 2 Dose 3 Dose 4 Dose 5
pertussis (<7 y)

Haemophilus influenzae See Dose 3 or 4

Dose 1 Dose 2
type b notes See notes

13-Valent pneumococcal conjugate

Dose 1 Dose 2 Dose 3 Dose 4
vaccine

Inactivated polio vaccine

Dose 1 Dose 2 Dose 3 Dose 4
(<18 y)

Inactivated influenza vaccine Annual vaccination 1 or 2 doses Annual vaccination 1 dose only
or or
Annual vaccination
Live attenuated influenza vaccine Annual vaccination 1 dose only
1 or 2 doses

Measles, mumps, rubella See notes Dose 1 Dose 2

Varicella Dose 1 Dose 2

Hepatitis A See notes 2-dose series, see notes

Meningococcal (MenACWY-D
See notes Dose 1 Dose 2
≥9 mo; MenACWY-CRM ≥2 mo)

Tdap (≥7 y) Tdap

See
Human papillomavirus
notes
See notes
Meningococcal B

23-Valent pneumococcal
See notes
polysaccharide vaccine

Range of recommended ages Range of recommended ages Range of recommended ages Range of recommended ages for nonhigh-risk groups that may
No recommendation
for all children for catch-up immunization for certain high-risk groups receive vaccine, subject to individual clinical decision making

FIGURE. Recommended child and adolescent immunization schedule for ages 18 years or younger, United States, 2019. For those
who fall behind or start late, provide catch-up vaccination at the earliest opportunity, as indicated by the dark green bars. School entry
and adolescent vaccine age groups are marked with a star. Tdap ¼ Tetanus toxoid, reduced diphtheria toxoid, and acellular Pertussis
vaccine adsorbed. From MMWR Morb Mortal Wkly Rep.4

DIPHTHERIA-TETANUS-ACELLULAR Tetanus continues to occur despite

PERTUSSIS routine universal vaccination.7 There is no
Diphtheria, because of routine universal herd immunity for this condition, and
vaccination, is a rare condition that causes spores of the bacterium Clostridium tetani
a membranous pharyngitis with an inflam- are found widely in the soil and in the in-
matory phase that can lead to cardiovascu- testines and feces of a variety of domesti-
lar collapse.7 Diphtheria was once a cated and wild mammals and chickens. As
common school-age child’s condition. It a result, neonatal tetanus occurs worldwide
resulted in hundreds of thousands of cases, because of the lack of maternal immunity
which led to 10,000 to 20,000 deaths yearly combined with unsterile birthing conditions
in the United States. Now, as a result of involving separation of the umbilical cord
routine vaccination, cases occurring in the and placenta. In 2010, nearly 60,000 infants
United States are highly unusual. Diph- died worldwide of neonatal tetanus. Before
theria still occurs in other parts of the the United States adopted routine universal
world. The causative organism is Coryne- vaccination in the 1940s, perhaps 500 to
bacterium diphtheria, and the severe disease 600 cases occurred each year in the United
that it can cause is the result of a toxin pro- States, including neonatal and nonneonatal
duced by certain strains infected with a forms. In recent years, 20 to 30 cases have
bacteriophage. occurred each year in the United States. In

Mayo Clin Proc. n February 2020;95(2):395-405 n https://doi.org/10.1016/j.mayocp.2019.06.007 397

www.mayoclinicproceedings.org

this country now, neonatal tetanus is a very
rare event, and most cases of tetanus now
occur in older individuals with minor in-
juries combined with a lack of sufficient
tetanus vaccination.
Whooping cough or pertussis results
from infection with the bacteria Bordetella
pertussis.7 Before routine vaccination in the
1940s, 200,000 cases a year were reported
in the United States. The disease could be
fatal in infants. The reported cases were pri-
marily in infants and children, and it is likely
that many more cases occurred because
pertussis in adolescents and adults is milder
and harder to recognize.17 Although routine
infant vaccination begun in the 1940s has
dramatically reduced the occurrence of in-
fantile disease, there has recently been a
resurgence in reported cases of pertussis pri-
marily in older children and adolescents.
Several reasons are cited: polymerase chain
reaction techniques that facilitate diagnosis,
greater awareness of pertussis, the relatively
short duration of immunity in both those
infected and those vaccinated, and faster
waning and less potency associated with
the acellular form of the pertussis vaccine
as opposed to the whole-cell form.18-20
Current recommendations call for all in-
fants to be immunized against diphtheria,
tetanus, and pertussis.20 The recommenda-
tions call for a 3-dose priming series given
at 2, 4, and 6 months of age.20 The child
then should receive booster doses at 12 to
15 months of age and again at 4 t0 6 years
of age, preceding kindergarten attendance
(Figure).4,20 Older children, adolescents,
and adults demonstrate too much reactivity
to the doses used in infants and children
younger than 7 years, and so a vaccine espe-
cially designed for adolescents and adults
uses reduced doses of diphtheria toxoid
and pertussis antigensdthe Tdap vaccine.
Efforts to reduce the reactogenicity of the
vaccine to make the vaccine more acceptable
led to the replacement in the 1990s of the
whole-cell pertussis vaccine with an acellular
vaccine consisting of a combination of
pertussis antigens.20 This acellular pertussis
vaccine, however, is less effective and results
in a briefer period of immunity.18,19
n n
398 Mayo Clin Proc.
MAYO CLINIC PROCEEDINGS
Recent advances include the routine
vaccination of pregnant females.20 This im-
parts to the newborn infant passive immu-
nity against pertussis for the first 6 months
because it takes at least 6 months for the
baby to receive the primary 3 doses at 2, 4,
and 6 months of age and respond to that.
Maternal vaccination in pregnancy has
been shown to reduce the risk of hospitaliza-
tion by 58% in infants with pertussis.21
Recommendations call for the maternal
vaccination to be given between 27 and 36
weeks of gestation, preferentially at 27 weeks
or as early in this window as possible. This
allows for the mother-to-be to generate a
vigorous response to the vaccine, making
enough antibody for passive transfer to the
fetus, even if the baby is delivered prema-
turely.20,21 Remaining problems include the
continued circulation of pertussis among ad-
olescents and adults.18 The reduced-dose
Tdap vaccine gives no more than moderate
protection against the disease in the first
year, and protection then wanes rapidly
over 2 or 3 years.22 Researchers are investi-
gating a more effective and long-lasting
pertussis vaccine that solves the problem of
unacceptable reactivity.23-25
POLIO
Current US recommendations call for uni-
versal vaccination with the trivalent, inacti-
vated injected form of polio vaccine of all
infants, with 3 doses of vaccine given at 2,
4, and 12 to 15 months of age and a booster
at 4 to 6 years of age (Figure).4,26 The ACIP
recommends catch-up through 18 years of
age.4 The ACIP permits with its full support
an additional dose of inactivated polio vac-
cine (IPV) at 6 months as a result of 1 of 2
combination vaccines, given the overriding
benefits of reduced injections and possibly
delays in vaccine receipt.26
The enterovirus is transmitted through
the fecal-oral route.7 Humans are the only
known reservoir of the virus. In infants,
the virus often causes a transient infection
without paralysis. In older children, adoles-
cents, and adults, these infections can result
in severe paralysis that can leave the patient
dependent on artificial support for
February 2020;95(2):395-405 https://doi.org/10.1016/j.mayocp.2019.06.007
www.mayoclinicproceedings.org
ROUTINE CHILDHOOD VACCINES
ventilation. Although patients paralyzed
from polio may eventually recover, compli-
cations may recur over a lifetime. The US
incidence of polio peaked in the 1950s at
20,000 cases per year. The last known case
in this country occurred in 1979. Poliovi-
ruses, however, still infect humans in other
parts of the world.
The IPV used in this country is a triva-
lent vaccine directed against the 3 types of
poliovirus.27 In parts of the world with
recent circulating wild poliovirus, the World
Health Organization recommends the use of
a live oral polio vaccine (OPV) given its ten-
dency to pass in the stool and boost the polio
immunity of caretakers and others in prox-
imity to the recipient.5 In this way, the
OPV sustains herd immunity. Since May
2016, only monovalent and bivalent forms
of OPV with types 1 and 3 are manufactured
and distributed given the eradication of type
2.28 In countries still at risk for endemic
polio, the conduct of national polio vaccine
days where all children receive a dose of
OPV combined with active surveillance for
paralytic illness has led to the successful
elimination of circulating wild poliovirus.29
Real progress has occurred, with type 2
declared eradicated globally in 2015. Type
1 has been responsible for outbreaks in
2017 and 2018 in Afghanistan and Pakistan.
Type 3 was last identified in 2012.
In seeking to maintain population immu-
nity against all 3 types for now, the ACIP
recommends that clinicians and public
health authorities no longer presume that
OPV is necessarily an adequate substitute
for the recommended doses of the trivalent
IPV.30 Doses of OPV given after April 2016
must be recorded in writing as trivalent
OPV or they do not count. All doses of
OPV given since May 2016 are by necessity
monovalent or bivalent and do not include
type 2. They also do not count toward
completion of the recommended series of
poliovirus vaccinations in the United States.
Plans for removing the universal vaccina-
tion against polio in this country will require
proof at a global level of eradication of all 3
types of poliovirus infection.31 Until we
obtain global eradication, all US children
Mayo Clin Proc. n February 2020;95(2):395-405
www.mayoclinicproceedings.org
should continue to undergo routine vaccina-
tion against poliovirus.26
HAEMOPHILUS INFLUENZAE TYPE B
One of the most striking periods in modern
pediatric history was the dramatic near-
elimination of H influenzae type b (Hib) dis-
ease as a result of routine immunization of
infants and preschool-age children. Infection
with these bacteria can result in meningitis,
pneumonia, epiglottitis, septic arthritis, and
purulent pericarditis.32 Before routine vacci-
nation, each year in the United States
approximately 20,000 infants and young
children developed serious invasive infec-
tions.7 These infections often resulted in life-
long disabilities. Now, as a result of universal
vaccination of infants against Hib, the occur-
rence of disease has been dramatically
reduced in the United States. Eight cases of
Hib were reported in 2015.32
Vaccination calls for 2 or 3 priming doses
at 2 and 4 months (or 2, 4, and 6 months
depending on the vaccine) and a single
booster at 12 to 15 months (Figure).4 The
antigen targeted by Hib vaccination is a poly-
saccharide. The vaccines currently in use
represent a major technological achieve-
ment. Those younger than 2 years cannot
mount immunity against polysaccharides
successfully. Their immune systems ignore
polysaccharide-based vaccines such as the
23-valent pneumococcal polysaccharide vac-
cine (Pneumovax 23; Merck Sharp &
Dohme Corp). Initial efforts to control Hib
disease began with the licensure and recom-
mendation of universal vaccination with a
polysaccharide Hib vaccine. Conjugating
the polysaccharide with a protein overcame
the inability of infants to recognize and
respond to the polysaccharide. Although
the routine vaccination of children 2 years
and older greatly reduced the circulation of
Hib and decreased the number of cases of
Hib, routine universal vaccination of infants
with the protein-conjugated polysaccharide
vaccines virtually eliminated the disease in
the United States.
The success with protein conjugation led
to the successful development of the conju-
gated pneumococcal and meningococcal
n https://doi.org/10.1016/j.mayocp.2019.06.007 399

vaccines. Successful combinations of Hib
vaccine with the diphtheria-tetanus-
acellular pertussis (DTaP), HepB, and inacti-
vated poliovirus vaccines has reduced the
number of injections needed in a single visit
and has reduced delays in vaccination.
Few remaining problems persist with
Hib vaccination other than those typical
with a successful vaccination program in
which the absence of the disease resulting
from successful vaccination permits compla-
cency toward timely vaccination. Again, the
few cases of invasive Hib disease occur in
the unimmunized and the underimmu-
nized.32 This problem, however, is not
unique to Hib vaccination but is pervasive
across childhood vaccinations to varying
degrees.
PNEUMOCOCCUS
The second vaccine to take advantage of
conjugation of a polysaccharide with a pro-
tein to overcome the lack of T-
celleindependent immunity was developed
against serious invasive pneumococcal infec-
tions in infants.33 Serious invasive infections
with Streptococcus pneumoniae include
bacteremia, meningitis, pneumonia, and
cellulitis. The US ACIP schedule currently
calls for the routine vaccination at 2, 4,
and 6 months, with a booster at 15 months
of a 13-valent pneumococcal conjugate vac-
cine (PCV13) (Prevnar 13; Wyeth LLC)
(Figure).4,34
Before routine vaccination with the first
7-valent pneumococcal conjugate vacci-
ne(PCV7) (Prevnar 7; Wyeth LLC), experts
estimated that approximately 17,000 cases
of invasive pneumococcal disease occurred
each year in the United States in children
younger than 5 years , with 13,000 cases be-
ing bacteremia and 700 cases being meningi-
tis.7 These cases resulted in the deaths of
approximately 200 children each year.
Humans often carry S pneumoniae in the
nasopharynx. Twenty percent to 60% of chil-
dren test positive. Although there are at least
92 serotypes of S pneumoniae, only a
fraction of these cause invasive disease. Indi-
viduals at higher risk for invasive infection
n n
400 Mayo Clin Proc.
MAYO CLINIC PROCEEDINGS
include those with immunocompromising
conditions, functional or anatomical asplenia
including those with sickle cell anemia,
chronic heart, lung, liver, or kidney disease,
American Indians, and Alaskan Natives. The
first pneumococcal conjugate vaccine, PCV7,
licensed in 2000, contained 7 of the sero-
types that caused invasive pneumococcal
disease. The current vaccine is a PCV13
licensed in 2010.
Uptake rates of pneumococcal vaccina-
tion have been stable since 2013 in US chil-
dren 19 to 35 months of age at
approximately 82%.13 Rates of invasive
pneumococcal disease in children younger
than 5 years in the United States have drop-
ped significantly since introduction of the
PCV13 in 2010.35 The overall rate is 33%
lower. The rates of disease due to serotypes
in PCV13 dropped 84%. The rates of types
not included has also dropped.
Time-series modeling indicates that in
the first 3 years of the introduction of
PCV13 by replacing PCV7, 30,000 additional
children were spared invasive pneumococcal
disease, preventing 3000 deaths.36
A concern with this vaccine in both the
original 7-valent form and the current
13-valent form is that the reduction in circu-
lation of the included serotypes would result
in the emergence of other serotypes not
covered by the vaccine. Although this did
seem to be the case with serotype 19A after
the introduction of PCV7, studies after the
introduction of PCV13 have not detected a
similar pattern.35,36 Several studies have
shown that this fear has not been realized.
Additional serotypes not currently covered
by the vaccine might be candidates for a
multivalent vaccine that covers a spectrum
greater than the current PCV13.36 Preclinical
trials are underway studying such expanded
conjugate vaccines. A second concern arose
with the recognition that this vaccine can
interfere with the response to the pneumo-
coccal polysaccharide 23-valent vaccine, at
least in adults,37 resulting in rules avoiding
the simultaneous administration of these 2
vaccines where both may be used in children
2 years and older as well as in adults at
February 2020;95(2):395-405 https://doi.org/10.1016/j.mayocp.2019.06.007
www.mayoclinicproceedings.org
ROUTINE CHILDHOOD VACCINES
higher risk for pneumococcal disease, prefer-
entially with PCV13 preceding the pneumo-
coccal polysaccharide 23-valent vaccine.34
ROTAVIRUS
As dramatic as the impact of the vaccination
against Hib, another modern-day success
story of gigantic proportion has been the
routine universal vaccination in the United
States against rotavirus. Before routine vacci-
nation, infection with rotavirus manifested
itself as a seasonal infectious diarrhea.7
Five strains or serotypes of the virus exist,
with 1 serotype (G1) causing most of the
disease. It was estimated that before routine
vaccination, rotavirus caused 3 million cases
of diarrhea in children every year in the
United States, resulting in more than
400,000 health care provider visits, 200,000
emergency department visits, and more
than 55,000 hospitalizations. In developing
countries, rotavirus infection is often fatal,
but deaths in the United States are rare,
perhaps because of better nutritional health
before infection as well as greater access to
health care and better approaches to rehy-
dration and care.
The ACIP recommends that all infants
receive vaccination against rotavirus dis-
ease.38 The number of doses depends on
the vaccine used. Two vaccines are licensed
in the United States: Rotarix (GlaxoSmithK-
line) is a 2-dose monovalent, live, viral vac-
cine to be given at 2 and 4 months of age,
and RotaTeq (Merck Sharp & Dohme
Corp) is a 3-dose pentavalent live viral vac-
cine to be given at 2, 4, and 6 months of
age (Figure). Both vaccines share limited
windows for catch-up. The ACIP expresses
no preference for one vaccine over the other.
The vaccines generate immunoprotective
antibodies.7 The vaccines are administered
orally. RotaRix is a single attenuated human
strain. RotaTeq includes 5 reassortant rotavi-
ruses constructed from human and bovine
strains. A previous live oral rotavirus vaccine
that included 4 serotypes was licensed in the
United States but was removed from the
market by the manufacturer when postlicen-
sure monitoring detected an apparent
increased rate of intussusception primarily
Mayo Clin Proc. n February 2020;95(2):395-405
www.mayoclinicproceedings.org
in older recipients. Analysis of the associa-
tions led to strict age and timing restrictions
of the vaccine. As a result of the experience
with the previously licensed vaccine, it is
recommended that no infant older than 14
weeks, 6 days should start the vaccine series
and no child older than 8 months, 0 days can
receive any further doses to complete the se-
ries.38 Since 2013, approximately 73% of
children 19 to 35 months of age in the
United States had completed a timely series
of rotavirus vaccination.13
Studies before and after licensure have
shown that although there may be some as-
sociation with intussusception in recipients
even with these newer formulations of the
vaccine, the rates are miniscule and pale in
comparison to the substantially greater
benefit of reduction in rotavirus infection.39
The use of these 2 vaccines in the Unites
States has reduced the hospitalization rate
for diarrhea by 40,000 to 60,000 admissions
per year.7
Remaining questions include the variable
success of rotavirus vaccination in devel-
oping countries where the impact of vaccina-
tion has not been as impressive and the need
is even greater given the high rates of mortal-
ity associated with rotavirus disease.40,41
Work conducted with the original rotavirus
vaccine (RotaShield; Wyeth) showed prom-
ising effectiveness in neonates as a 2-dose
administration with the first dose given at
birth.42 Research continues with altered
schedules, and new candidate vaccines and
adjuvants are being pursued to overcome
the problems with rotavirus vaccination in
developing countries.40
INFLUENZA
The final vaccine routinely recommended in
the United States to infants before the first
birthday is the inactivated influenza vaccine
routinely recommended as starting at 6
months or older (Figure).4,43 Infants, as
first-time recipients of the vaccine, require
2 doses of the influenza vaccine at least 28
days apart administered as an intramuscular
injection. The 2-dose series should begin as
soon as the vaccine becomes available for
the season and ideally no later than the
n https://doi.org/10.1016/j.mayocp.2019.06.007 401

end of October. Vaccine providers should
continue to offer the vaccine to those who
do not receive the vaccine until the vaccine
is no longer available to the provider that
season. The live attenuated influenza vaccine
available as a nasal spray (FluMist; MedI-
mmune), is not indicated in those younger
than 2 years because of an increased risk of
hospitalization and wheezing.44,45
Influenza is particularly severe in infants
and children. A study of medically attended
influenza found that the rate in children 6
months to 9 years of age ranged from 33 to
70 per 1000 children across 3 recent sea-
sons.46 Influenza-related hospitalization
rates in children younger than 2 years rival
the hospitalization rates in those 65 years
and older. 7 Annual rates vary from 100 to
500 per 100,000 children.7 Deaths from
influenza are much rarer in children than
in adults 65 years and older. Of the 675
deaths in children due to influenza in the
United States from 2010 through 2016, how-
ever, 78 (12%) occurred in infants younger
than 6 months and another 116 (17%)
occurred in those 6 to 23 months of age.47
Since 2004, when child death from influenza
became a reportable condition in the United
States, the highest number recorded was in
the 2017-2018 season, with 183 deaths.48
Of these, 80% were not vaccinated against
influenza.
Three vaccines are currently licensed for
use in infants.43 All are quadrivalent inacti-
vated vaccines. The selection of the antigens
used in the vaccines is based on consider-
ation of strains circulating in the previous
season and strains that will grow in chicken
eggs to produce immunogenic vaccines.
The US vaccination rate in infants 6 to 24
months of age was 74% for the 2017-2018
season. This was 2.3% less than the previous
year and refers only to the first of the 2 doses
needed for infants getting the vaccine for the
first time.49 Most children needing 2 doses of
influenza vaccine do not get the second dose
in the same season.50 It is difficult with such
low uptake and with high variability year to
year in seasonal influenza activity to demon-
strate the effectiveness of the vaccine in in-
fants 6 months and older, but a recent
n n
402 Mayo Clin Proc.
MAYO CLINIC PROCEEDINGS
meta-analysis of published studies shows
the vaccine to be approximately 67% to
76% effective in infants against infection.51
Infants younger than 6 months are at high
risk for influenza and its complications, but
studies with current vaccines in infants
younger than 6 months show poor immuno-
genicity and efficacy.52 The American Acad-
emy of Pediatrics has recommended
cocooning young infants by proactively vacci-
nating household members at medical visits
for those infants. Furthermore, vaccinating
mothers-to-be during pregnancy (primarily
done to protect the pregnant female) has
been shown to not only protect the woman
during and after pregnancy from complica-
tions of influenza as well as prevent prema-
ture birth and fetal loss but also to protect
the infant in the first months after birth.52
Still, work is underway to find safe and effec-
tive vaccines to administer to young infants.
GENERAL ISSUES
In the United States, in the first 11 months
after birth we vaccinate against 9 vaccine-
preventable diseases (Figure).4,53 This in-
volves, in addition to the birth dose of
HepB, at least 4 or 5 additional visits for
administration. Although combinations exist
(DTaP-IPV/Hib and DTaP-Hib-HepB), some
infants may receive 6 injections at a given
visit when DTaP, IPV, Hib, and HepB are
given as separate injections. Efforts to
combine the vaccines can reduce the number
of injections at a visit to no more than 4.
Other approaches to reduce or prevent pain
for infant vaccinations include, of course,
routes that avoid injection, such as the oral
administration of the rotavirus vaccines.
The current polio vaccine, however, is
injected, having replaced the oral dosing
with live attenuated polio vaccine, as dis-
cussed previously herein. Vaccine providers
should use evidence-based approaches to
reduce pain when vaccinating. For infants
these approaches include permitting the
mother to breastfeed while the baby receives
the vaccine, alternatively providing sweet-
tasting solutions by mouth to the baby, using
less painful brands of otherwise equally
effective and safe vaccines when more than
February 2020;95(2):395-405 https://doi.org/10.1016/j.mayocp.2019.06.007
www.mayoclinicproceedings.org
ROUTINE CHILDHOOD VACCINES
1 brand exists, positioning upright rather
than supine for injection, performing rapid
rather than slow injection, and ordering the
vaccines in administration from least to
most painful.54 Although caregivers might
propose separating the vaccinations so that
fewer injections are given at a time, such
an approach is likely to increase the overall
amount of pain and distress that the infant
experiences. Furthermore, the separation
leads to delays and failures to vaccinate.
Expert recommendations hold that all vac-
cines due should be given at 1 visit.
In the United States, where clinicians in
primary care deliver most routine childhood
vaccinations in their office, clinicians should
use presumptive language to signal their
strong recommendations for the routine
childhood immunizations due, and if hesita-
tion or resistance emerges, use the C.A.S.E.
(Corroborate, About me, Science, and
Explain advice) approach to address vaccine
hesitancy in the office setting.55,56
Presumptive language uses statements
such as “The nurse will next give the vaccines
due” and contrasts with participatory language
that implies that the vaccines are optional if not
debatable, such as “What are your thoughts
about the vaccines recommended?”56 The
odds of parents accepting the recommenda-
tions when presumptive language is used are
as high as 17.5 times the odds of accepting if
participatory language is used.56 The C.A.S.E.
approach is a brief communication technique,
first proposed by Allison Tepper Singer, that
combines the provider’s and parent’s underly-
ing shared values, the provider’s professional
standing, the provider’s understanding of the
science, and the reiteration of their advice to
address parental concerns.55
CONCLUSION
Of course, routine childhood vaccination
does not end in the first 11 months after
birth. A follow-up to this review will cover
the vaccine-preventable diseases and the
vaccines given starting at age 12 months
through age 18 years. These diseases
include measles, mumps, rubella, varicella,
Mayo Clin Proc. n February 2020;95(2):395-405
www.mayoclinicproceedings.org
hepatitis A, meningococcus, and human
papillomavirus.
Abbreviations and Acronyms: ACIP = Advisory Com-
mittee on Immunization Practices; DTaP = diphtheria-
tetanus-acellular pertussis; HepB = hepatitis B; Hib = Hae-
mophilus influenzae type b; IPV = inactivated polio vaccine;
OPV = oral polio vaccine; PCV7 = 7-valent pneumococcal
conjugate vaccine; PCV13 = 13-valent pneumococcal con-
jugate vaccine; Tdap = tetanus toxoid, reduced diphtheria
toxoid, and acellular pertussis vaccine adsorbed
Potential Competing Interests: Dr Jacobson has served as
a board member for the Southeast Minnesota Immunization
Connection; has received grant support from the National
Cancer Institute (CA 217889); and has served on safety re-
view committees and a data monitoring committee for
Merck & Co.
Correspondence: Address to Robert M. Jacobson, MD,
Mayo Clinic, 200 First St SW, Rochester, MN 55905
(jacobson.robert@mayo.edu).
The Thematic Reviews on Vaccines will continue in an
upcoming issue.
REFERENCES
1. Centers for Disease Control and Prevention. Ten great public
health achievementsdUnited States, 1900-1999. MMWR
Morb Mortal Wkly Rep. 1999;48(12):241-243.
2. Centers for Disease Control and Prevention. Achievements in
public health, 1900-1999: control of infectious diseases.
MMWR Morb Mortal Wkly Rep. 1999;48(29):621-629.
3. Centers for Disease Control and Prevention. Ten great public
health achievementsdUnited States, 2001-2010. MMWR
Morb Mortal Wkly Rep. 2011;60(19):619-623.
4. Robinson C, Bernstein H, Romero J, Szilagyi P. Advisory
Committee on Immunization Practices recommended immu-
nization schedule for children and adolescents aged 18 years
or youngerdUnited States, 2019. MMWR Morb Mortal Wkly
Rep. 2019;68(5):112-114.
5. World Health Organization. WHO recommendations for
routine immunizationdsummary tables. https://www.who.
int/immunization/policy/immunization_tables/en/. Accessed
October 12, 2018.
6. Centers for Disease Control and Prevention. Advisory Commit-
tee on Immunization Practices (ACIP) website. https://www.cdc.
gov/vaccines/acip/index.html. Accessed October 12, 2018.
7. Centers for Disease Control and Prevention. Epidemiology and
Prevention of Vaccine-Preventable Diseases. 13th ed. Washington,
DC: Public Health Foundation; 2015.
8. Centers for Disease Control and Prevention. VaxView. https://
www.cdc.gov/vaccines/vaxview/index.html. Accessed October
12, 2018.
9. Schillie S, Vellozzi C, Reingold A, et al. Prevention of hepatitis B
virus infection in the United States: recommendations of the
Advisory Committee on Immunization Practices. MMWR
Recomm Rep. 2018;67(1):1-31.
10. Splawn LM, Bailey CA, Medina JP, Cho JC. Heplisav-B vaccina-
tion for the prevention of hepatitis B virus infection in adults in
the United States. Drugs Today (Barc). 2018;54(7):399-405.
11. Centers for Disease Control and Prevention. Achievements in public
health: hepatitis B vaccinationdUnited States, 1982-2002. MMWR
Morb Mortal Wkly Rep. 2002;51(25):549-552.563.
n https://doi.org/10.1016/j.mayocp.2019.06.007 403

12. Wasley A, Kruszon-Moran D, Kuhnert W, et al. The prevalence
of hepatitis B virus infection in the United States in the era of
vaccination. J Infect Dis. 2010;202(2):192-201.
13. Hill H, Elam-Evans L, Yankey D, Singleton J, Kang Y. Vaccination
coverage among children aged 19e35 monthsdUnited States,
2017. MMWR Morb Mortal Wkly Rep. 2018;67(40):1123-1128.
14. Ko SC, Fan L, Smith EA, Fenlon N, Koneru AK, Murphy TV.
Estimated annual perinatal hepatitis B virus infections in the
United States, 2000-2009. J Pediatr Infect Dis Soc. 2016;5(2):
114-121.
15. Schillie S, Walker T, Veselsky S, et al. Outcomes of infants born
to women infected with hepatitis B. Pediatrics. 2015;135(5):
e1141-e1147.
16. Markey PG, White HA, Matthews AT, Strebor CR, Krause V.
Prevention of perinatal hepatitis B virus transmission: are we
following guidelines? Commun Dis Intell Q Rep. 2017;41(3):
E195-E198.
17. Domenech de Celles M, Magpantay FMG, King AA, Rohani P.
The impact of past vaccination coverage and immunity on
pertussis resurgence. Sci Transl Med. 2018;10(434).
18. Cherry JD. The present and future control of pertussis. Clin
Infect Dis. 2010;51(6):663-667.
19. Edwards KM. Unraveling the challenges of pertussis. Proc Natl
Acad Sci U S A. 2014;111(2):575-576.
20. Liang JL, Tiwari T, Moro P, et al. Prevention of pertussis, tetanus,
and diphtheria with vaccines in the United States: recommen-
dations of the Advisory Committee on Immunization Practices
(ACIP). MMWR Recomm Rep. 2018;67(2):1-44.
21. Winter K, Cherry JD, Harriman K. Effectiveness of prenatal
tetanus, diphtheria, and acellular pertussis vaccination on
pertussis severity in infants. Clin Infect Dis. 2017;64(1):9-14.
22. Klein NP, Bartlett J, Fireman B, Baxter R. Waning Tdap effective-
ness in adolescents. Pediatrics. 2016;137(3):e20153326.
23. Meade BD, Plotkin SA, Locht C. Possible options for new
pertussis vaccines. J Infect Dis. 2014;209(suppl 1):S24-S27.
24. Robbins JB, Schneerson R, Kubler-Kielb J, et al. Toward a new
vaccine for pertussis. Proc Natl Acad Sci U S A. 2014;111(9):
3213-3216.
25. Gaillard ME, Bottero D, Moreno G, Rumbo M, Hozbor D. Stra-
tegies and new developments to control pertussis, an actual
health problem. Pathog Dis. 2015;73(8):ftv059.
26. Centers for Disease Control and Prevention. Updated recom-
mendations of the Advisory Committee on Immunization Prac-
tices (ACIP) regarding routine poliovirus vaccination. MMWR
Morb Mortal Wkly Rep. 2009;58(30):829-830.
27. Prevots DR, Burr RK, Sutter RW, Murphy TV. Advisory Com-
mittee on Immunization Practices. Poliomyelitis prevention in
the United States: updated recommendations of the Advisory
Committee on Immunization Practices (ACIP). MMWR
Recomm Rep. 2000;49(RR-5):1-22.
28. World Health Organization. Polio vaccines: WHO position paper,
March 2016-recommendations. Vaccine. 2017;35(9):1197-1199.
29. Fournier-Caruana J, Previsani N, Singh H, et al. Progress toward
poliovirus containment implementationdworldwide, 2017-
2018. MMWR Morb Mortal Wkly Rep. 2018;67(35):992-995.
30. Marin M, Patel M, Oberste S, Pallansch MA. Guidance for
assessment of poliovirus vaccination status and vaccination
of children who have received poliovirus vaccine outside
the United States. MMWR Morb Mortal Wkly Rep. 2017;
66(1):23-25.
31. Pallansch MA. Ending use of oral poliovirus vaccine: a diffi-
cult move in the polio endgame. N Engl J Med. 2018;
379(9):801-803.
32. Butler DF, Myers AL. Changing epidemiology of Haemophilus
influenzae in children. Infect Dis Clin North Am. 2018;32(1):
119-128.
33. Advisory Committee on Immunization Practices. Preventing
pneumococcal disease among infants and young children: rec-
ommendations of the Advisory Committee on Immunization
Practices (ACIP). MMWR Recomm Rep. 2000;49(RR-9):1-35.
n n
404 Mayo Clin Proc. February 2020;95(2):395-405
MAYO CLINIC PROCEEDINGS
34. Nuorti JP, Whitney CG. Prevention of pneumococcal disease
among infants and children: use of 13-valent pneumococcal
conjugate vaccine and 23-valent pneumococcal polysaccharide
vaccinedrecommendations of the Advisory Committee on
Immunization Practices (ACIP). MMWR Recomm Rep. 2010;
59(RR-11):1-18.
35. Pilishvili T, Gierke R, Farley M, et al. Direct and indirect impact
of 13-valent pneumococcal conjugate vaccine (PCV13) on
invasive pneumococcal disease (IPD) among children and
adults in the U.S. Open Forum Infect Dis. 2017;4(suppl 1):
S66-S67.
36. Moore M, Link-Gelles R, Schaffner W, et al. Effect of use of 13-
valent pneumococcal conjugate vaccine in children on invasive
pneumococcal disease in children and adults in the USA: anal-
ysis of multisite, population-based surveillance. Lancet Infect Dis.
2015;15(3):301-309.
37. de Roux A, Schmole-Thoma B, Siber GR, et al. Comparison of
pneumococcal conjugate polysaccharide and free polysaccha-
ride vaccines in elderly adults: conjugate vaccine elicits
improved antibacterial immune responses and immunological
memory. Clin Infect Dis. 2008;46(7):1015-1023.
38. Cortese MM, Parashar UD. Prevention of rotavirus gastroenter-
itis among infants and children: recommendations of the Advi-
sory Committee on Immunization Practices (ACIP). MMWR
Recomm Rep. 2009;58(RR-2):1-25.
39. Centers for Disease Control and Prevention. Addition of his-
tory of intussusception as a contraindication for rotavirus vacci-
nation. MMWR Morb Mortal Wkly Rep. 2011;60(41):1427.
40. Tissera MS, Cowley D, Bogdanovic-Sakran N, et al. Options for
improving effectiveness of rotavirus vaccines in developing
countries. Hum Vaccin Immunother. 2017;13(4):921-927.
41. Burnett E, Yen C, Tate JE, Parashar UD. Rotavirus vaccines: cur-
rent global impact and future perspectives. Future Virol. 2016;
11(10):699-708.
42. Armah GE, Kapikian AZ, Vesikari T, et al. Efficacy, immunoge-
nicity, and safety of two doses of a tetravalent rotavirus vaccine
RRV-TV in Ghana with the first dose administered during the
neonatal period. J Infect Dis. 2013;208(3):423-431.
43. Grohskopf LA, Sokolow LZ, Broder KR, Walter EB,
Fry AM, Jernigan DB. Prevention and control of seasonal
influenza with vaccines: recommendations of the Advisory
Committee on Immunization PracticesdUnited States,
2018-19 influenza season. MMWR Recomm Rep. 2018;
67(3):1-20.
44. Grohskopf LA, Sokolow LZ, Fry AM, Walter EB, Jernigan DB.
Update: ACIP recommendations for the use of quadrivalent
live attenuated influenza vaccine (LAIV4)dUnited States,
2018-19 influenza season. MMWR Morb Mortal Wkly Rep.
2018;67(22):643-645.
45. FluMist Quadrivalent [package insert]. Gaithersburg, MD: MedI-
mmune; 2018.
46. Jackson ML, Phillips CH, Benoit J, et al. Burden of medi-
cally attended influenza infection and cases averted by
vaccinationdUnited States, 2013/14 through 2015/16
influenza seasons. Vaccine. 2018;36(4):467-472.
47. Shang M, Blanton L, Brammer L, Olsen SJ, Fry AM. Influenza-
associated pediatric deaths in the United States, 2010-2016. Pe-
diatrics. 2018;141(4).
48. Centers for Disease Control and Prevention. Summary of the
2017-2018 influenza season. https://www.cdc.gov/flu/about/
season/flu-season-2017-2018.htm. Accessed November 1,
2018.
49. Centers for Disease Control and Prevention. Estimates of flu
vaccination coverage among childrendUnited States,
2017e18 flu season. https://www.cdc.gov/flu/fluvaxview/
coverage-1718estimates-children.htm. Accessed November 1,
2018.
50. Jackson LA, Neuzil KM, Baggs J, et al. Compliance with the rec-
ommendations for 2 doses of trivalent inactivated influenza
vaccine in children less than 9 years of age receiving influenza
https://doi.org/10.1016/j.mayocp.2019.06.007
www.mayoclinicproceedings.org
ROUTINE CHILDHOOD VACCINES

vaccine for the first time: a Vaccine Safety Datalink study. Pedi- recommended immunization schedule for children and adoles-
atrics. 2006;118(5):2032-2037. cents aged 18 years or youngerdUnited States, 2018. MMWR
51. Luksic I, Clay S, Falconer R, et al. Effectiveness of seasonal influenza Morb Mortal Wkly Rep. 2018;67(5):156-157.
vaccines in childrenda systematic review and meta-analysis. Croat 54. Taddio A, Appleton M, Bortolussi R, et al. Reducing the pain of
Med J. 2013;54(2):135-145. childhood vaccination: an evidence-based clinical practice
52. Moriarty LF, Omer SB. Infants and the seasonal influenza vac- guideline. CMAJ. 2010;182(18):E843-E855.
cine: a global perspective on safety, effectiveness, and alternate 55. Jacobson RM, Van Etta L, Bahta L. The C.A.S.E. approach: guidance
forms of protection. Hum Vaccin Immunother. 2014;10(9):2721- for talking to vaccine-hesitant parents. Minn Med. 2013;96(4):49-50.
2728. 56. Opel DJ, Heritage J, Taylor JA, et al. The architecture of
53. Robinson CL, Romero JR, Kempe A, Pellegrini C, Szilagyi P. provider-parent vaccine discussions at health supervision visits.
Advisory Committee on Immunization Practices Pediatrics. 2013;132(6):1037-1046.

Mayo Clin Proc. n February 2020;95(2):395-405 n https://doi.org/10.1016/j.mayocp.2019.06.007 405

www.mayoclinicproceedings.org