In addition to the designated antigen(s), a vaccine contains additives that may include adjuvants,
preservatives, stabilizers, conjugating agents and
Which of the following statements are correct?
a) All pediatric single-dose vaccines licensed for
routine use in the United States are either free
of thimerosal or contain only trace amounts (< 1
microgram [mcg] of mercury/dose as residual
from the manufacturing process).
b) Measles, mumps and rubella vaccines as well
as varicella and rotavirus vaccines always have
been free of preservatives such as thimerosal.
c) Conjugated vaccines have proven to be over-
whelmingly successful for control of disease due
to Streptococcus pneumoniae and Haemophilus
influenzae type b.
d) Aluminum salts are the only licensed adjuvants
for use in vaccines.
Adjuvants are designed to enhance the immune
response to a vaccine antigen (immunogen) and to
allow for use of smaller amounts of antigen. The
most commonly used adjuvants in the United States
are aluminum salts, such as aluminum hydroxide
or aluminum phosphate. Originally, it was thought
that aluminum salts acted as a repository for the vaccine antigen, but now it is believed that they also play
a role in modulating the inflammatory response.
In the first six months of life, the total amount of
aluminum contained in all routinely recommended
vaccines is about 4 milligrams (mg). This is about
one-half the amount of aluminum received from
breast milk and less than one-tenth the amount of
aluminum received from regular infant formula
during the first six months of life. In over 70 years
of use, aluminum salts have proven to be safe and
In 2009, Cervarix (bivalent human papillomavirus
vaccine) was licensed in the United States (although
it is no longer available in this country). The vaccine
contains a novel adjuvant system (AS04) known as
monophosphoryl lipid A (a detoxified endotoxin)
designed to enhance the immune response. The
vaccine has been administered safely to hundreds
of thousands of people.
Fluad was licensed by the Food and Drug Administration in November 2015 as the first seasonal
influenza vaccine containing a novel adjuvant. Fluad
is licensed for people 65 years of age or older but may
become available for children. The vaccine contains
MF59 as an adjuvant, consisting of an oil-in-water
emulsion of squalene oil. Squalene occurs naturally
in humans and is one of the major components of
skin surface lipids.
Preservatives are added to vaccines to prevent the
growth of bacteria or fungi that might cause contamination during use of a multi-dose vial. Four
preservatives are currently used in some vaccines:
thimerosal, 2-phenoxyethanol, phenol and benze-thonium chloride. Some preservatives cannot be
used with certain antigens. For example, thimerosal
is not used in inactivated polio virus vaccine (IPV)
as it may reduce the potency of certain poliovirus
serotypes. Instead, 2-phenoxyethanol is used in IPV
Stabilizers protect a vaccine from degradation and
temperature extremes during manufacture, shipping
and storage. They consist of proteins (human serum
albumin, gelatin), sugars (sucrose, lactose) or amino
acids (glycine, glutamic acid). Because such small
quantities of antigen are contained in a vaccine,
stabilizers minimize adherence to glass in a vial or
syringe. One H. influenzae type b vaccine contains
only 10 mcg of polysaccharide antigen per dose. Live
vaccines may contain only nanograms of antigen
(103-105 viral particles per dose).
Protective immunity against encapsulated bacteria
such as Neisseria meningitidis, S. pneumoniae and H.
influenzae type b is induced by capsular polysaccharides. When used in inactivated vaccines, capsular
polysaccharides are poorly immunogenic and do
not result in long-term immunity. Conjugation of
capsular polysaccharide to a protein carrier changes
the nature of the immune response and converts the
polysaccharide to a potent immunogen that can be
used effectively in a vaccine. One disadvantage of
conjugate vaccines is the complexity of the manufacturing process, resulting in high cost.
Types of proteins used as carriers include tetanus
toxoid, diphtheria toxoid and CRM197 (naturally
occurring nontoxic diphtheria toxin). Recent re-
ports suggest the protein carrier does not need to
be directly linked to polysaccharide to enhance the
immune response. Fixing the polysaccharide cap-
sular antigen to a protein matrix may enhance a
vaccine’s immunogenicity as effectively as a covalent
bond (Thanawastien A, et al. Proc Natl Acad Sci USA.
2015;112:e1143-e1151). If proven to be effective,
this would allow manufacture of conjugate vaccines
in a less complicated process, reduce vaccine cost and
enable wider use in developing countries.
Preservatives do not eliminate the risk of contamination, so antimicrobial agents may be added
to a vaccine formulation. Antibiotics contained in
licensed vaccines include streptomycin, polymyxin
B, neomycin and gentamicin. Beta lactam antibiotics are not present in vaccines. Thus, a history of
penicillin allergy is not an acceptable reason to avoid
Vaccines may contain tiny amounts of residual
material that remains from the licensed manufacturing process, including yeast protein, formaldehyde
and cellular DNA.
It is important to remember that despite their
complexity, vaccines are remarkably safe and effective, and adverse reactions to vaccines are monitored
constantly. The risk of anaphylaxis to any vaccine is
estimated to be one case per 1 million to 2 million
vaccine doses administered.
Dr. Meissner is professor of pediatrics
at Floating Hospital for Children, Tufts
Medical Center. He also is an ex officio
member of the AAP Committee on Infectious Diseases and associate editor of
the AAP Visual Red Book.
A n s w er: a, b a n d c are c orre ct