Vaccination of Very Premature Infants
F. Edward Yazbak, MD, FAAP
number of infants born prematurely has been steadily increasing in the United
States. Very small and very premature infants are now surviving in increasing
The CDC has
decided that in the majority of cases, infants born prematurely, regardless of
birth weight, should be vaccinated with the same dose(s), at the same
chronological age and according to the same schedule and precautions as
full-term infants and children.
D’Angio et al of the Vaccine Research Unit at the University of Rochester have
reported that during the first six months of life, extremely
preterm infants mount lower antibody responses to vaccines than term infants.
Accordingly, the risks and benefits of the ever increasing number of mandated
pediatric vaccines from birth to six months, need to be carefully re-examined
for that specific group of infants.
When it comes to information about vaccines and vaccination research, it is
becoming extremely difficult, even for professionals, to sort out the facts.
March 6, 2007, a good friend in New Zealand who is well aware of my interest in
MMR vaccination sent me a report originally filed by WMTW-TV Channel 8 in
Auburn, Maine. The station is the ABC affiliate covering the greater Portland,
ME area, a gorgeous part of New England, situated just three hours away by car
from my home.
title of the news item was
“Vaccines Safe For Preemies, Study Says –
MMR, Chicken Pox Shots Work In Pre-Term Infants
measles-mumps-rubella and or chicken pox are effective
in extremely preterm infants, according to a new study
The rest of the news report read:
had assumed they would work, even though preemies' immune systems may not be
"No one had
formally researched the subject," said study author Dr. Carl D'Angio of the
University of Rochester Medical Center. "I'm happy to be able to reassure my
colleagues and parents that it is OK."
The study included
16 full-term and 16 extremely preterm infants born between May 2002 and May
2005. It examined the antibody levels of the diseases before and after
vaccination. It was published in this month's issue of Pediatrics.
The same number of
infants in each group reached a level considered protective.
"Now we can all
breathe a sigh of relief. We were right," D'Angio said.”
is entirely possible that an uninformed reader or young parent would interpret
the above jubilant report as proving that the MMR and chickenpox vaccines were
safe and effective in extremely preterm infants, like those often seen on
television with breathing tubes and IV lines in incubators.
fact, the infants who participated in the investigational study – all 32 of them
- were healthy and 15 months old when they were vaccinated.
Relative to the safety statement, the infants were just seen twice, 3 to 6
weeks apart, and “safety” was
assessed “by parental recall of vaccine-related adverse events and by active,
prospective collection of blood-draw-associated adverse events”.
It should be noted
that all MMR vaccine safety studies conducted by the vaccine industry have been
notoriously short. Only two studies extended to eight weeks.
friend in Wales also sent me information about the same Rochester University
study that she had received via EurekAlert Science News Service.
tone of that news item was more restrained but its message was no less decisive.
“MMR, chicken pox vaccines work for preemies”
“Vaccines for measles-mumps-rubella and varicella, or chicken pox, are effective
in extremely preterm infants, even though preemies' immune systems are not as
developed as full-term babies. This confirms a long-held assumption by
pediatricians and neonatologists across the country.”
assumption has always been that it would be OK, that very early babies would
have enough immunity, but no one had formally researched the subject," said Carl
D'Angio, M.D., associate professor of Pediatrics at the University of Rochester
Medical Center, and author of a paper on the subject in Pediatrics this month.
"I'm happy to be able to reassure my colleagues and parents that it is OK."
Principal Investigator (PI) was again quoted as saying
we can all breathe a sigh of relief. We were right,"
According to the news report, the study was funded by the National Institute of
Allergy and Infectious Diseases and the National Center for Research Resources
of the National Institutes of Health.
Official Study Record
MMR and Varicella Vaccine in Premature Infants
This study has been completed.
University of Rochester
Information provided by:
University of Rochester
purpose of the study was listed as follows:
“This research is
designed to address the question, “Does the relative deficit in vaccine
immunogenicity in extremely premature infants persist beyond the first 6 months
Immunogenicity is the ability of a vaccine to provoke an immune
response and result in immunity.
above question, as stated, suggests that administration of one or several
vaccines once, twice or three times to very small (< 1lb) and very premature
(<28 wk gestation) infants during the first six months of life, does not provoke
immune responses and therefore does not protect from illness. In a literal
sense, all the administered antigens cannot be referred to as “immunizations”.
that is so, then a true re-evaluation of risks and benefits of vaccinations
administered in that population is in order and the statement by some that
infants without exception have the capacity to respond to an enormous number
of antigens (1) is invalid.
PI goes on to describe the purpose of the study as follows:
“We propose to
measure the immunogenicity of varicella and mumps-measles-rubella vaccines in
relatively healthy, 12-to-15 month-old children born at <29 weeks gestation,
when compared to full-term infants, as measured by the relevant viral serologies.”
In fact the
enrolled infants were not “relatively” healthy. They had to be healthy.
Subjects must meet
all of the inclusion criteria to participate in this
infant < 29 weeks’ gestation at birth or term infant >/= 37 weeks’ gestation at
Postnatal age < 16 months, 0 days.
Has not yet received MMR or varicella vaccines. (There are no
restrictions on the administration of other vaccines at the time of MMR/varicella
Agreement of primary care pediatrician/ health care provider.
Receives primary pediatric care within an approximate 25-mile radius of
the University of Rochester.
Healthy status at
Systemic corticosteroid therapy at the time of MMR/varicella vaccination.
Requiring oxygen therapy.
Clinically significant findings on review of medical history and physical
exam determined by the investigator or sub-investigator to be sufficient for
condition determined by the investigator that would interfere with the
evaluation of the vaccine or be a potential health risk to the subject.
According to the
protocol “subjects will be approached at 9-12 months of age for inclusion”. They
included sixteen ex-very premature infants had to be healthy, not only on the
day they were vaccinated, but actually three to six months earlier, when they
were registered. In other words, when the study was being conducted, those
infants were the healthiest very small infants around Rochester, New York.
It should be
pointed out that pediatricians are constantly told that they can and should
vaccinate infants that are not in such pristine condition. Obeying such
directives, pediatricians insist on vaccinating small preemies on oxygen and
monitors, or who have colds and sniffles, on or close to schedule. Some actually
threaten recalcitrant parents with referral to child protective agencies or
exclusion from the practice.
Study start: January 2004; Study completion: December
Last follow-up: May 2005; Data entry closure: May 2005
and Varicella Vaccine Responses in Extremely Premature Infants
generally healthy premature infants born at < 29 weeks’ gestation, < 16 months
old from the Rochester area 16 generally healthy 37 weeks’ gestation,³full-term
infants born at < 16 months old from the Rochester area
Number of Sites: University of Rochester
Study Duration: 1.5 – 8.5 months
Agent or Intervention:
Subjects will make
2 study visits. The first, at 15 months of age, will coincide with a routine
well child visit. Subjects will have 2 mL of blood drawn at the time of their
routine, 15-month MMR, varicella, and pneumococcal conjugate immunizations. At a
second study visit 4-6 weeks later, another 2 mL of blood will be drawn.
propose to measure the immunogenicity of routinely administered varicella and
mumps-measles-rubella vaccines in relatively healthy, 12-to-15 month-old
children born at <29 weeks gestation (premature), when compared to that in
Safety will be
assessed by parental recall of vaccine-related adverse events and by active,
prospective collection of blood-draw-associated adverse events.
Schematic of Study
Subjects will be
approached at 9-12 months of age for inclusion, and will consent at this time or
at Visit 1”
The study was
published in the March 2007 issue of PEDIATRICS.
A Medline abstract is
children had lower mumps and rubella geometric mean titers than did
term children before vaccine, and nearly all children were seronegative
for each of the 4 vaccine antigens before immunization. Measles,
mumps, rubella, and varicella geometric mean titers were similar
between groups after vaccine. All children were seropositive for
measles after vaccine, whereas 13 of 14 preterm and 11 of 13 term
children were seropositive for mumps, 13 of 14 preterm and 13 of 13
term children were seropositive for rubella, and 11 of 16 preterm and 9
of 15 term children were seropositive for varicella.
CONCLUSIONS: Preterm children mounted antibody responses that were similar to those of term
children after measles-mumps-rubella and varicella vaccines at 15 months of age.
CDC has long recommended the administration of the first dose of MMR and
chickenpox vaccines at the age of one year and parents are cajoled and coerced
to comply. This study does not guarantee that the risk taken by having 4 live
attenuated virus vaccines administered simultaneously to small children is
warranted. Indeed, as noted, even vaccination at 15 months of age did not result
in full protection against rubella, mumps and chicken pox.
not clear why the investigators proposed to examine the immunogenic response
between 12 and 15 months but actually waited to vaccinate the children until
they were 15 to 16 months old. This is certain to raise questions.
timing of the vaccinations brings out another indirectly related but yet very
According to the American Academy of Pediatrics, the “routine” pediatric visit
at which the MMR and chickenpox (and other) vaccines are administered should be
scheduled at the age of twelve months. Why then was that “routine visit”
actually “scheduled” at age 15 months in Rochester, the site of a major vaccine
Investigator is a member of the Department of Pediatrics at the University of Rochester.
He is presently finishing a similar study on the pneumococcal
conjugate vaccine and is in the process of studying the influenza vaccine. All
32 infants in this study also received a dose of pneumococcal conjugate vaccine
at the age of 15 months.
University of Rochester’s Vaccine Research Unit is renowned.
research effort at the University of Rochester Medical Center brings together a
rare combination of resources that covers the gamut from basic research, to
vaccine testing, to improving and measuring the availability of vaccines to
people who need them most…. All vaccines depend on our knowledge of the basic
workings of the immune system…
research done more than a decade ago by a trio of University virologists has
become crucial to two promising vaccines designed to prevent cervical cancer. A
vaccine to prevent this type of cancer, which kills more than 250,000 women
around the globe every year, is expected to become available within a year,
thanks in large part to technology developed at the University. The vaccine
targets a group of viruses known as human papillomaviruses (HPV), which cause
On the applied
side, the University’s Vaccine and Treatment Evaluation Unit has had a hand in
testing dozens of new vaccine candidates, including nearly every new vaccine to
be approved in the last three decades. The unit is part of a network that the
Federal government turns to for protecting the nation against infectious
Just as important
as creating or testing the vaccines, is getting them to the people who need them
most. Here again, University doctors are part of virtually every large national
network created to monitor the effectiveness of vaccines. The Rochester
community finds itself one of the best vaccinated and best monitored in the
world, and researchers worldwide have a grasp on just how well vaccines work,
thanks to research by Rochester doctors.”
Funding for vaccine
research at the University of Rochester Medical Center is provided by the
National Institutes of Health and has almost doubled in five years (see graph).
NIH Funding Continues to Grow at URMC
For parents in the autism community, the University of Rochester will
always be remembered as the place that produced the Pichichero Thimerosal study.
(2) Most of us are still scratching our heads about that study’s methodology and conclusions.
More recently, the University of
Rochester Vaccine Research Unit offered to the world (and Merck coffers) the
gift of the Human Papilloma Virus (HPV) vaccine.
See “How Cow Warts, Clergy Sex
Surveys Moved Along Cancer Vaccine” at
“The creation of a successful vaccine against cervical
cancer, approved today by the U.S. Food and Drug Administration, is the culmination
of research that occurred thanks not only to scientists and physicians, but also to generous
farmers and veterinarians, priests and nuns willing to tell all – and some very
patient cows”(Thursday June 8, 2006)
On Tuesday February 8, 2007, the University of Rochester Medical Center published
“Preventing V.D. as Valentine’s Day Approaches”.
Day just around the corner, the world’s largest study of a vaccine to protect
against genital herpes – a disease that infects approximately one of every four
women and men in the nation – takes on special significance for Rochester-area
women and their male companions.
Doctors and nurses
are recruiting women in the Rochester area who don’t have genital herpes to help
test a vaccine against the sexually transmitted disease. So far, 237 women
locally have joined the study, making Rochester one of the lead sites
nationally. But more female participants ages 18 to 30 are needed to effectively
test the vaccine.”
The statement ended
“Men are not part of the study because previous studies have shown that the
vaccine does not work in men.”
That alone may have ruined the
Valentine's Day in Rochester.
All clinical trials of pediatric
healthy infants and children and everyone makes certain that the infant or child
is healthy at the time the vaccine is administered.
There are no studies where sick or
“slightly sick” infants are vaccinated.
It is therefore strange that
pediatricians are asked to vaccinate less than perfectly healthy infants and
even stranger that they insist to do so.
In the recent Rochester study, the 16
ex-small preemies and the 16 normal infants used as controls received the MMR
and chickenpox vaccines at the age of 15 months. In real life, the CDC
recommends that these two vaccines be administered at 12 months of age when the
ex-preemies are often more vulnerable.
“In the majority of cases, infants born prematurely, regardless of birth weight,
should be vaccinated at the same chronological age and according to the same
schedule and precautions as full-term infants and children. Birth weight and
size are not factors in deciding whether to postpone routine vaccination of a
clinically stable premature infant, except for hepatitis B vaccine. The full
recommended dose of each vaccine should be used. Divided or reduced doses are
In the case of live virus vaccines
such as MMR, a follow-up period of 3 to 6 weeks is not long enough to evaluate
One can only wonder why small very
premature infants need the rubella, the mumps and the chickenpox vaccines at the
age of twelve months.
The single most
important conclusion that anyone can draw from “Measles-mumps-rubella and
varicella vaccine responses in extremely preterm infants” is that extremely
premature infants have a relative deficit in vaccine immunogenicity until the
age of 6 months.
The issues that have been
identified in this report will tend to compromise the significance of the study
findings and their relevance to pediatric practice.
“The Rochester community finds itself one of the best vaccinated and best
monitored in the world…”
The United States
Congress passed the
Children's Health Act of 2000 and mandated the establishment of centers of excellence in
autism research. In response, the Institutes of the
NIH Autism Coordinating Committee have
implemented the STAART (Studies to Advance Autism Research and Treatment)
One of the
eight US Autism Research Centers of Excellence is located at the University of
Rochester. Patricia Rodier, Ph.D., is the Director of the Center and Susan
Hyman, M.D., FAAP is the Co-director.
about 50% of Rochester area families with preschool children on the autistic
spectrum use a gluten free and casein free diet.
Beeler JA. Measles-mumps-rubella and varicella vaccine
responses in extremely preterm infants.
Treanor J. Mercury concentrations and metabolism in
infants receiving vaccines containing thiomersal: a descriptive study.
2002 Nov 30;360(9347):1737-41.
Atkinson WL et al General Recommendations
on Immunization CDC - MMWR February 8, 2002 / 51(RR02);1-36
Edward Yazbak, MD, FAAP