Preterm immunisation 2018 - Dr Karthik Nagesh

1. Vaccination in Preterms – Current Thoughts
• I am a Neonatologist
• I am not a
Vaccinologist/Immunologis
t
• No Financial support
Dr N Karthik Nagesh
Manipal Hospital
Bangalore

2. Very appropriate forum to address the Issue
• Increasing Number Of Extreme PT (GA <28 Weeks)
with VLBWs and Comorbid Conditions (eg BPD,
Seizures) in Indian NICUs
• As the benefit of vaccination is high in this group ,
vaccination should not
be withheld or delayed

3. Aim to address Concerns….
• Immunogenicity,
• Safety
• Tolerabilty
• Responses to routine immunizations in
preterms with and without
comorbidities….Emerging Evidence

4. Preterm infants are at an increased risk of
morbidity and mortality from vaccine- preventable
diseases.
Despite this, delays in
routine immunization of
preterm infants are
common
Available guidelines
clearly state that they
should be immunized
according to chronological
age
Irrespective of GA , BWt or
current weight.

5. Poor Rates of vaccination in preterm
infants
• Rates were lower if the child was hospitalised at the time the
vaccination was due
• Although vaccination may have been administered on time while the
infant was an inpatient, there is an indication that subsequent doses
following the infant’s discharge can be delayed
• The greater the prematurity and lower the birth weight, the more
likely it is that vaccination will be given later than recommended
• Vaccination may be justly delayed in some cases when a preterm
infant’s unstable condition contraindicates
Tozzi AE et al ,Timeliness of routine immunization in a population-based Italian cohort of very preterm infants: results of
the ACTION follow-up project. Vaccine 2014; 32:793-9

6. Why we are still not vaccinating preterms in NICUs ?
• Ill Informed on safety & efficacy of immunisation in preterms
• Mental block
• Is there a need?....Never felt the need!
• Worry/Scare about reactions
• Have you seen anything go wrong in unvaccinated preterms ?
• We have not seen any rota diarrhea on followup
• Scared of potential opv / rota horizontal transmission
• Not convinced yet!
• Seroconversion alone is not the answer- Is there data on
actual protection?
• IM injections in thin muscle mass of preterms is a worry
I still am not vaccinating my preterms in the NICU!!

7. Some have just started doing it …cautiously!!
• Convinced regarding data on safety & efficacy
• But, still worried about Adverse effects
• Closely monitoring during/after vaccination
• Noted reactions- 10%-20%
• Only in stable preterms not needing any supports
• Only in babies in ‘step down/post natal’ wards
• Heterogenous Schedules used
• Staggering vaccines over 2-3 days
• Only ‘one set’ of vaccines before Discharge
• Not given all recommended Vaccines

8. We are not giving all these years – Yet no
harm has befallen!!
• Pertussis
• Invasive Pneumococcal Disease
• Influenza
• Rota Virus Diarrhea
Marshall H et al,Pediatr Infect Dis J,2015
High Risk of ‘Vaccine Preventable Diseases’
in Unimmunised Preterms

9. Vaccine Preventable Diseases – Are we doing
Justice to our Preterms in NICU/Graduates?
• Severe acquired
Pneumonitis in ELBWs
discharged from NICU (
Manipal Hospital, Bangalore,2013-18)
• of 77 Naso-Pharyngeal
Swab samples sent ..…
18 positive for RSV by
real time PCR
• Severe morbidity
H1N1 Infection- ARDS-on ECMO,7 months age
In NICU GRADUATE-extremely preterm(26 wks) with CLD
PICU-Manipal Hospital, B’lore

10. Do Preterms(ELBW) need Immunization to be
given while in hospital itself?
Medically stable PT and low
birth weight (LBW) infants
should receive full doses of
diphtheria, tetanus, acellular
pertussis, Haemophilus
influenzae type b, hepatitis
B, poliovirus, and
pneumococcal conjugate
vaccines at a chronologic
age consistent with the
schedule recommended for
full-term infants.
Infants with birth weight
less than 2000 g may
require modification of the
timing of hepatitis B
immunoprophylaxis
depending on maternal
hepatitis B surface antigen
status.
American Academy of Pediatrics Committee
on Infectious Diseases
Immunization of preterm and low birth
weight infants..
Saari TN; Pediatrics. 2003 Jul;112(1 Pt 1):193-
8.

11. Despite this - in Reality there is ‘Delay’
• PT continue to have
inadequate
immunization coverage
in NICU & at discharge
from the NICU as also in
the outpatient setting,
• More so, after discharge
• Delays persisting until
age 1 year sometimes
The most important factor
explaining the delay in
administering routine
vaccines is;
• lack of knowledge
regarding the safety and
effectiveness of
vaccines in preterm
infants among
healthcare workers and
parents.
Langkamp DL, Hoshaw-Woodard S, Boye ME, Lemeshow S. Delays in receipt of
immunization in low-birth weight children. Arch Pediatr Adolesc Med 2001

12. Preterms are too small for multiple vaccines-
They won’t work
Can Preterms Mount Enough Immune Response
to Vaccines?
Immunogenicity alone is not important !
Data on Benefits is not convincing !
Are they Protective antibody levels ?
Sure They Do!!

13. Prematurity is indeed associated with immunologic
immaturity of multifactorial etiology!!
• Innate immaturity of the infant’s system, with
decreased T and B cells, antibodies, and ability
to mount an adequate response to antigens.
• Humoral immunity is also impaired
• PT are dependent on maternal antibodies for
initial defense.

14. Maternal IgG antibody transfer
begins as early as 13 weeks in
utero, but maximum transfer occurs
in the final timester especially after
36 weeks’ gestation.
Even late PT (34-36 weeks) lack
adequate maternal protective IgG.
This passive antibody
transfer is efficient and the
cord blood of term babies shows
levels of IgG that correlate with
maternal levels
This Protection is more
effective for measles and
tetanus and less so for
polio and pertussis

15. Immunocompetence in Preterm newborns
• Prenatal maturation…each additional week of
gestation sees an increased response to
antigens.
• Postnatal maturation…begins upon exposure
to environmental antigens, occurs in preterms
at a speed comparable to that of full-term
infants
Gaudelus J et al. Arch Pediatr 2014

16. But, Preterms do mount good antibody
response!!
• Current evidence indicates that immune response in PT is
directly proportional to GA and BW
• Various factors can influence antibody production:
Clinical conditions
Treatment given
Vaccine composition
Vaccination schedules
• However, regardless of the variations induced by these factors,
vaccines appear to induce a protective immune response in
preterm infants in the majority of cases.
• Vaccination produces a subgroup of memory cells that result in an
enhanced response to the booster doses in PTs

17. .All studies focus on the
vaccine’s ability to provoke an immune
response (immunogenicity) in premature
infants,
.But this is not the same as the
efficacy of the vaccine – its ability to reduce
the incidence of disease
.In vaccine development immunogenicity is
generally relied on as a predictor for
vaccine efficacy

18. Use of the Rota Virus vaccine in PT (25-36 weeks GA)
has been shown to decrease hospitalization and
emergency department visits for rotavirus
gastroenteritis by 100%
Protection from the vaccine extends up to three
epidemic seasons after immunization
Vaccine Efficacy in Preterms

19. Follow Same Chronological Age as in Full Term?
It is important that
premature babies have
their immunisations at the
appropriate chronological
age and not corrected
gestational age
**With the exception of the
BCG vaccine
Preterm infants are able to mount
a protective immune response to
vaccination.
While absolute primary antibody
responses may be lower in
preterms compared to term babies
vaccinated according to
chronological age
The majority achieve antibody
concentrations higher than levels
generally accepted to correlate
with protection

20. Safety and effectiveness of BCG vaccination in
preterm babies
Sudhin Thayyil-Sudhan, Ashok Kumar, Meharban Singh, Vinod Kumar Paul,
Ashok Kumar Deorari
Arch Dis Child Fetal Neonatal Ed 1999;81:F64–F66
• Similar uptake and cell mediated immune responses
(PPD,LMIT) against BCG vaccine in preterm babies vaccinated
early at 34 wks and late at 38–40 weeks POG
• Delaying age of vaccination did not seem to improve the
conversion rates & might increase the number of missed
vaccination opportunities.
• The conversion rates in preterm babies are similar to those
reported for term neonates
• BCG can be given Effectively at 34-35 weeks Gestation/Safe

21. Immunogenicity and safety of early vs delayed BCG
vaccination in moderately preterm (31–33 weeks)
infants
• No difference in the PPD conversion rate after 6
months of BCG immunization in moderately preterm
infants immunized early soon after birth (39.1%) or
given vaccination late at completion of 34 weeks post
conception age (37.5%).
• Recommend that BCG vaccine may be safely given to
moderately preterm infants (31–33 weeks) at birth.
Megha Saroha, MMA Faridi, Prerna Batra, Iqbal Kaur & DK Dewan (2015),
Human Vaccines & Immunotherapeutics, 11:12, 2864-2871

22. BCG in Preterms- ongoing RCT
• Two arms- A)> Early Gestation,
B)> At 36 weeks POG
• *Survival Outcome at 1 year
*All Cause Mortality reduced in earlier African Study
Mangalabharathi,ICH, Chennai, Personal Comm.

23. Preterm babies vaccinated at
34-35 weeks post conception
show seroconversion rates
similar to those in term
newborns.
Is zero dose oral polio vaccine effective in
preterm babies?
Thayyil-Sudhan S, Singh M, Broor S, Xess I, Paul VK, Deorari AK.
Ann Trop Paediatr. 1998 Dec;18(4):321-4.

24. Vaccine safety assessment
in preterms
Particularly challenging
due to the frequency of
adverse events
intrinsically associated
with prematurity
Schulzke S, Heininger U, Lucking-Famira M, Fahnen- stich H. Apnoea
and bradycardia in preterm infants following immunisation with
pentavalent or hexavalent vaccines. Eur J Pediatr 2005
Worried About Adverse Events !.. Are they
Safe in Preterms ?

25. Risk of Apnea is indeed there!
• The occurrence of apnea following vaccination is
especially increased in very Preterms
• If the baby has previously had apnea,bradycardia, or
desaturation after other immunisations
• Particularly those with a previous history of
respiratory immaturity.
• Nevertheless the studies also report that the adverse
events are of limited clinical significance and should
not be an influencing factor in the decision to
immunise
Gaudelus J, Lef evre-Akriche S, Roumegoux C, Bolie S, Belasco C,
Letamendia-Richard E, Lachassinne E. Immunization of the
preterm infant. Arch Pediatr. 2007

26. Factors associated with increased incidence of
post-immunisation apnea
• Apnea within the 24 hour period before immunisation
• More severe illness at birth
• Chronological age less than 67 days, and/or earlier GA
with a BW < 1500g
• Although apneic episodes are not causally associated
with immunisation, an apneic episode following the first
immunisation event is a significant risk factor for an
apneic episode following the second immunisation
• No long term sequelae

27. Severe episodes of apnea
• Reported in relation to DTWP immunization of
preterms <31 weeks of gestation
• Less frequent and less severe following DTAP.

28. Apnea monitoring of preterm and/or VLBWs
• Those with a history of respiratory immaturity - after the
first immunisation
• When a preterm has experienced apnea after the first
immunisation (for medical reasons and to maintain
parental confidence)
• Immunisation should not be withheld or delayed
• Monitoring all preterms still hospitalised in neonatal units
at the time of immunization seems prudent
Premedication and possibly
staggering vaccines may be the
best way to minimize side effects.

29. DTaP/DtwP/Hib
Immune responses to all of the
components of this vaccine are satisfactory
in preterm infants,
However protective
levels decrease as prematurity increases
The Hib component has variable results
which appear to depend on the schedule
used, particularly if it is an accelerated
Schedule
D’Angio Ctetal,Pediatrics 1995
Vazquez L etal.Acta Paediatr 2008
What is the Protective Effect of
Individual Vaccines in Preterms?

30. Neutralizing antibodies are required to
control for the viremic phase of poliovirus
infection
Data suggest IPV offers preterm infants
protection against polioviruses types I, II
and III.
D’Angio CT, et al,Pediatrics 1995
IPV

31. MenC
Lower but acceptable
responses have been
observed with this vaccination
even in VLBWs
PCV
• Although preterms show an
immunogenic response considered
to be protective to PCV7, this is
lower than in terms.
• But, replacement of the 7-valent
PCV with a 13-valent version
…data now debatable

32. When to give Hep-B Vaccination?
• If Mother is HBsAg Positive
• If Mother’s HBsAg Status is unknown
• If Mother is HBsAg Negative

33. In PT, this is a dilemma as hepatitis B virus (HBV) is
the only vaccine known to have a significantly lower
response in PT compared to FT infants (45%-85% vs
90%-100% when given at birth)
Lower BW and earlier GA are contributing factors.
In PT who weighed more than 2,000 g the response
was the same as in FT infants.
In PT with GA of 23 to 26 weeks, immunization if
delayed until 30 days or hospital discharge,
seroconvertion rates comparable to FT infants and
maintained protection
Hepatitis B virus (HBV) vaccine is the only vaccine for
which data clearly indicate a lower response in preterms

34. Preterms born to mothers whose hepatitis B carrier status is not
known should also receive hepatitis B immunoprophylaxis
regardless of their birth weight.
Infants born to hepatitis B negative (HBsAg negative) mothers
prematurely and/or weighing less than 2000g can be adequately
protected against hepatitis B after three doses of vaccine
beginning at 6 weeks of age.
For infants who get HBV before they weigh at least 2 kg, the first
dose is discounted and they should get the usual three-dose
schedule afterwards
Infants born to hepatitis B carrier mothers
Preterms born to HBsAg-positive mother require hepatitis B
immunoglobulin (HBIG) and a hepatitis B immunisation within 12 hours
of birth

35. • Pertussis has seen a resurgence recently.
• Waning immunity has been implicated
• Re-emphasis on booster doses.
• PT have repeatedly been shown to have a higher risk of
mortality and pertussis-related hospitalization than FT
infants. Despite lower antibody response,
primary immunization series were able
to induce antibodies in a cohort of 94
preterms with vaccine response rates
>98.9% although long-term pertussis-
specific immune responses seems to be
lower in preterms
Sposito S, etal,Vaccine 2002

36. Pertussis vaccine can be given in either a whole cell or an acellular
format
Currently, most countries are using the acellular format for which
immunogenicity is shown but difficult to quantify as the correlates for
protection are not well established.
Antibodies to the specific antigens are accepted as surrogate markers
for immunity even though levels have no specific consensus.
Acellular or Whole Cell Pertussis Vaccine?

37. Measles-Mumps-Rubella/Varicella
Prior to vaccination for measles, mumps, and rubella (MMR),
immunity is dependent on the transfer of maternal antibody to the
infant.
As most mothers are currently immunized and not naturally
immune, the number of antibodies available for transfer is lower.
In PT, this is compounded by a reduced duration of transfer of
antibodies.
Data show that in infants younger than GA 28 weeks, most had lost
their immunity as early as age 3 months, and in another group was
absent from birth.

38. MMR Vaccine-When?
• The result of this early loss of maternal antibodies is the
appearance of a critical window of risk for measles
infection during the first year of life,
• Suggest MMR immunization at an earlier age for
preterms
• Presently, the decision to not vaccinate PTs at < 9
months has been made due to relative immunological
immaturity concerns

39. Worried About Giving MMR Vaccine !
Link between the MMR vaccine and Autism Spectrum
Disorder, although completely disproven is still raised by
many parents
Preterms Risk of Follow up ‘Neuro-Sensory Issues’ is High
Need information & Counselling

40. Varicella vaccine
Is a live attenuated vaccine and considered highly
immunogenic
It is also recommended at a later age to ensure an
adequate and persistent immune response
Comparison data between FT and PT do not show any
difference in antibody responses when given after 1 year

41. Both formats of the vaccine (rotavirus 5 and
rotavirus 1) have shown similar
seroconversion rates in PTI and FT infants
Preterms with lower GA had significantly
lower titers and seroconversion rates
NICUs often delay initiating this vaccine
during hospitalization due to a
theoretical risk of horizontal
transmission
To be alert to the small window for
immunization
Evidence supports immunization per
routine schedule of the PTI prior to 32
weeks
Omenaca F et al. Safety, reactogenicity and immunogenicity of the
human rotavirus vaccine in preterm Euro- pean Infants: a randomized
phase IIIb study. Pediatr Infect Dis J. 2012

42. No Influenza vaccine has been shown to be effective in
producing a protective antibody response in infants
younger than age 6 months,
Focus should hence be on maternal and caregiver
immunization.
The trivalent vaccine is safe for breast-feeding
mothers and can be given during those critical first 6
months of life.
Once the infant is age 6 months, the vaccine should be
given to PT too regardless of maternal immunization.
With a risk of adverse events, why expose my patient to even
more controversial vaccines like influenza vaccine?

43. Palivizumab has been shown to have a significant effect on the
mortality and morbidity in the preterms
Economics- costs high!!
Do we need to give ‘RSV’ Prophylaxis?

44. Is it Safe to give in Sick Preterms, ELBWs, those
with Apnea/Seizures, in BPD?
It is exactly this fragility that puts them at even more risk from
vaccine-preventable diseases, making it imperative to immunize
them as soon as possible
Despite a perception of increased respiratory events with
immunizations, there is no difference in respiratory
decompensation in infants with or without BPD.
Preterms who have cardiovascular instability are more likely to
be those that were unstable at baseline.
Close monitoring is prudent but delayed vaccination is not
justified.

45. Antenatal steroid use has shown no effect on vaccines but
there is a small difference in titers after the use of post-
natal steroids.
These differences in titers, although significant, still attain
a level sufficient to provide protection against disease
If steroid dose of >2 mg/kg of BW/day is given for more
than 2 weeks, then a delay in live vaccines should be
considered.
Does Steroid use in Preterms affect vaccine
effects?

46. Seizures that are controlled and unrelated to a previous dose of
vaccination are not a contradiction for delay in immunizations.
The only time DTaP or Tdap (tetanus, diphtheria, and pertussis)
are contraindicated is in those with a history of an
encephalopathic event within 7 days of the vaccine that is not
attributable to any other cause.
Seizures present within 3 days of immunization are not absolute
contradictions but warrant some caution.
Stable neurological conditions, such as cerebral palsy,
developmental delays, or even history of high fevers are not
barriers for immunization
The Preterm has had a Seizure-Is it OK to vaccinate?

47. Why not we Vaccinate Mothers instead of
Preterms in NICU?
The safety of the Tdap vaccine in pregnancy has been well
established, and thus the recommendation is that all pregnant
women be vaccinated.
In PT, who may not achieve complete immunity until after completion
of all 3 doses, there is a cocooning safety net in place.
A recent meta-analysis has shown a decreased risk of LBW or
preterm birth in mothers who received the Influenza vaccine during
pregnancy.
All family members should be encouraged to get the flu vaccine,
particularly with PT whose birth and course leaves them
unimmunized over the course of two flu seasons.

48. What Dosing and is to be Followed in Preterms?
Same Dosing
No Splitting of Dose
Even in very sick babies

49. Extreme Preterms have so less Muscle Mass for
IM Injection-Worry!!
• Any Criteria (Weight)
?
• Any Preference Site ?
The preferred site for intramuscular
immunisation in preterm or low birth
weight infants is the same as for full
term infants, the vastus lateralis. A 23–
25 gauge x 16mm needle inserted at a
90° angle to the skin is usually
adequate.

50. Can Preterms in NICU get exposed to ‘Vaccine
Preventable Diseases
Arent Current Restrictions
on NICU Visitors Enough to
Protect?
Targeted immunisation or cocooning
• Research suggests that most infants
acquire diseases such as whooping
cough and infuenza from family
members.
• “Cocooning” or “targeted
immunisation” involves ensuring the
infant’s close contacts (parents,
grandparents,siblings and carers) to
reduce the risk of disease exposure
for the infant.
• Important vaccines to consider
include pertussis-containing vaccines
and influenza vaccines.

51. If the Premmie is given IVIG, Blood Transfusion,
Exchanged, Given G-CSF etc, Can we still give
Vaccines?
Unlikely IVIG will interfere with
immunisation-Only delay Live Vaccines
MMR/Varicella - 8 months
Blood or blood product will not interfere
with T cell response induced by BCG
Zero dose of OPV will induce local IgA
response and will not be affected

52. Summary
• Absolute primary antibody responses may be lower in
preterm compared to terms vaccinated according to
chronological age
• But, majority achieve antibody concentrations higher than
levels generally accepted to correlate with protection.
• Vaccines are immunogenic, safe and well tolerated in
preterm infants
• Early active immunisation is particularly important in
preterms as they are among the most vulnerable to
infectious diseases.

53. Recommendations to vaccinate preterms are
not being adhered to
Strategy to increase
vaccination in this
vulnerable population-
sensitising
doctors/nurses/parents
Initiation of
Vaccination In Hospital
Before Homecoming
Might Improve The
Vaccination Rate