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Indian Pediatr 2017;54:1041 -1051 |
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Campaign Mode MMR
Vaccination to Control Outbreak of Mumps in a Highly Vaccinated
Population
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Source Citation: Cardemil CV, Dahl RM, James L,
Wannemuehler K, Gary HE, Shah M, et al. Effectiveness of a third
dose of MMR vaccine for mumps outbreak control. N Engl J Med.
2017;377:947-56.
Section Editor: Abhijeet Saha
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Summary
This study evaluated the effectiveness of a third
dose of MMR vaccine for outbreak control, and assessed for waning
immunity. Of 20,496 university students who were enrolled during the
2015–2016 academic year, mumps was diagnosed in 259 students. Fisher’s
exact test was used to compare unadjusted attack rates according to dose
status and years since receipt of the second MMR vaccine dose, and
multivariable time-dependent Cox regression models were used to evaluate
vaccine effectiveness, according to dose status (3 doses vs 2
doses, and 2 doses vs 0 dose) after adjustment for the number of
years since the second dose. The attack rate was lower among the
students who had received three doses than among those who had received
two doses (6.7 vs 14.5 cases per 1000 population, P<0.001).
Students had more than 9-times the risk of mumps if they had received
the second MMR dose 13 years or more before the outbreak. At 28 days
after vaccination, receipt of the third vaccine dose was associated with
a 78.1% lower risk of mumps than receipt of a second dose (adjusted
hazard ratio, 0.22; 95% CI 0.12 to 0.39). The vaccine effectiveness of
two doses versus no doses was lower among students with more distant
receipt of the second vaccine dose. The authors concluded that students
who had received a third dose of MMR vaccine had a lower risk of mumps
than those who had received two doses. Students who had received a
second dose of MMR vaccine 13 years or more before the outbreak had an
increased risk of mumps.
Commentaries
Evidence-based Medicine Viewpoint
Relevance: This study [1] was necessitated by the
occurrence of mumps outbreaks in US universities, despite high
population-based coverage with MMR vaccine using two doses during
infancy and childhood [2-4]. The investigators analyzed the number of
confirmed and probable mumps cases that occurred throughout the outbreak
and examined the effect of the additional MMR dose. Three major outcome
measures were evaluated: (i) attack rate of mumps by number of
MMR doses received; (ii) attack rate by duration since the last
dose; and (iii) vaccine effectiveness (of the additional dose).
Prior to the outbreak, over 98% of the students (age 8-24 years, n=20496)
had received at least two MMR doses. After the onset of the outbreak,
about one-fourth of the students received an additional MMR dose.
There were 259 cases during the outbreak period
(August 24, 2015 to May 13, 2016); yielding an attack rate of 12.6 cases
per 1000. The attack rate (per 1000) showed a progressive decline with
the total number of MMR doses received viz. 47.6 with zero doses,
32.8 with one dose, 14.5 with two doses, 6.7 with three doses, and 0
with four and five doses. Further the attack rate also varied by the
duration since receipt of the last dose: 1.6 for dose received within 2
years, 3.9 for dose received within 3-5 years, 11.3 for dose received
13-15 years prior, and 17.6 for dose received >16 years prior. The
additional dose of MMR vaccine was calculated to have an incremental
vaccine effectiveness of 78%.
Critical appraisal: The authors introduced
several methodological refinements to their analyses. Prior and
additional MMR vaccinations were confirmed by documentary evidence,
rather than verbal report. Therefore, the precise number and timing of
doses could be recorded. The immunogenic response following vaccination
was taken into consideration by calculating the attack rates 7, 14, 21
and 28 days post-vaccination; instead of at one time point.
A formal case definition was used [5,6], although the
details were not explicitly stated. The definition describes cases as
‘confirmed’ or ‘probable’ based on whether (or not) laboratory
confirmation was obtained. However, it is unclear whether cases were
detected through passive surveillance i.e students with symptoms
reported to health facilities; or active surveillance i.e. cases
were sought by trained field staff. This can result in a significant
difference in the number of cases detected.
It is unclear whether University students represent
merely an epidemiological age slab (18-24 years); or whether they
represent a cohort of persons with behavior patterns that could prompt
and/or promote outbreaks of infectious disease(s). The distinction is
important because waning of immunity from infant and childhood MMR
vaccination would create a pool of susceptible persons in the next
higher age group viz. adolescents and young adults. If age is the
only issue, cases would be expected among this group, irrespective of
whether they attend university or not. On the other hand, if behavior
patterns are also responsible, a disproportionate clustering of cases
within university campuses is expected. The latter seems to be the case
because two-thirds of the mumps cases were reported among university
students [7]. This has two potential implications. First, outbreaks
would be propagated by the combination of a susceptible cohort, with the
added influence of living within a somewhat closed environment
(residential, social and epidemiological). This means that merely
vaccinating university students (after the onset of an outbreak) without
putting into place surveillance systems, isolation facilities and
behavior modification strategies through education would be futile. This
aspect is especially important because behavior modification (students
themselves minimizing contact with cases) after the onset of an outbreak
would favorably influence the duration and impact of the outbreak. To be
fair, the authors considered these points, reiterating that additional
MMR vaccine doses could be one of several potential tools for outbreak
control.
Despite the impressive findings highlighted in this
study, there are some less emphasized data that merit attention. It
appears that even in a developed country like USA with robust
vaccination systems and records, there was only about 80% compliance to
the MMR vaccination schedules in infancy (first dose) as well as
childhood (second dose). However, even this less-than-desirable coverage
resulted in substantial reductions in the burden of disease, thereby
creating a pool of individuals lacking the opportunity for intermittent
natural boosting of immunity. Therefore it is not surprising that the
disease burden shifted to the next higher age group viz.
adolescents and young adults.
Even though students were provided an enabling
environment to receive additional MMR vaccination (free clinics,
extended hours, health education, campaign mode), only about one-quarter
availed this facility, despite the declaration of an outbreak. This
behavioral pattern among an educated and empowered cohort augurs poorly
for the successful implementation of campaign-mode, voluntary adult
vaccination as a public health measure.
This study clearly demonstrated the waning of
vaccine-induced immunity (at least for mumps). Even if the immunity is
boosted through an additional dose at entry into University, it is
possible that once sufficient adolescents and young adults are
protected, the disease burden will shift to older age groups. In other
words, the overall burden of disease may remain unchanged, merely moving
from one demographic bracket to another.
Further, female young adults with insufficient
anti-mumps antibody titers are likely to transmit inadequate antibodies
to their infants, thereby making young infants susceptible to the
disease. Since the first dose of MMR is administered at 12-15 months,
there is the likelihood of observing cases in the latter half of the
first year of life also. This trend is highly likely given that young
mothers (in USA) in the present era, are likely to have received the
last dose of MMR vaccine in childhood; and this study shows that
vaccination more than 16 years prior was associated with significant
decline in immunity.
Conclusion: This analysis suggests that
administration of MMR vaccine in a campaign mode, coupled with robust
public health measures could mitigate the intensity of a mumps outbreak
among highly vaccinated young adults in a University setting. It also
demonstrates waning of vaccine-induced immunity and raises the specter
of age-shifts in mumps (and possibly other vaccine preventable
diseases).
Funding: None; Competing interests: None
stated.
Joseph L Mathew
Department of Pediatrics,
PGIMER, Chandigarh, India.
Email:
[email protected]
References
1. Cardemil CV, Dahl RM, James L, Wannemuehler K,
Gary HE, Shah M, et al. Effectiveness of a third dose of MMR
vaccine for mumps outbreak control. N Engl J Med. 2017;377:947-56.
2. Centers for Disease Control and Prevention. Mumps
Cases and Outbreaks. Available from:
https://www.cdc.gov/mumps/outbreaks.html. Accessed November 14,
2017.
3. Centers for Disease Control and Prevention. Mumps
Outbreak at a University and Recommendation for a Third Dose of
Measles-Mumps-Rubella Vaccine – Illinois, 2015-2016. Available from:
https://www.cdc.gov/mmwr/volumes/65/wr/mm6529a2.htm. Accessed
November 14, 2017.
4. No authors listed. Mumps Outbreaks Hit 3 Different
US College Campuses; Cases More Than Double Last Year at This Time.
Available from:
https://invisiverse.wonderhowto.com/news/mumps-outbreaks-hit-3-different-us-college-campuses-cases-more-than-double-last-year-time-0176808/.
Accessed November 14, 2017.
5. Revision of the Surveillance Case Definition for
Mumps. Available from:
http://c.ymcdn.com/sites/www.cste.org/resource/resmgr/PS/07-ID-02.pdf.
Accessed November 14, 2017.
6. Mumps2012 Case Definition. Available from:
https://wwwn.cdc.gov/nndss/conditions/mumps/case-definition/2012/.
Accessed November 14, 2017.
7. Shah M, Quinlisk P, Weigel A, Riley J, James L,
Patterson J, et al. Mumps outbreak in a highly vaccinated
university-affiliated setting before and after a measles-mumps-rubella
(MMR) vaccination campaign-Iowa, July 2015-May 2016. Clin Infect Dis.
2017 Aug 16. doi: 10.1093/cid/cix718. (Epub ahead of print)
Pediatrician’s
Viewpoint
This study [1] reaffirms the need and effectiveness
of a 3rd dose of a MMR vaccine to university students to prevent regular
outbreaks or breakthrough disease in highly vaccinated
adolescents/adults. In recent times, many reports on outbreaks of mumps
amongst two dose recipients of MMR vaccine are published [2]. Centers
for Disease Control and Prevention (CDC) has also very recently given
its recommendations on the utility of using a 3rd dose of MMR during an
ongoing outbreaks among college-going students [3]. Earlier, the CDC
provided guidance on employing a third dose of MMR for outbreak control
but stopped short of making a full recommendation.
What the study fails to provide?
1. The study fails to provide an ‘exact’ duration
of protection offered by a single dose of MMR vaccine against the
mumps disease. Though the authors have used a cut-off of 13 years,
this is based on the fact that the 2nd MMR dose is usually given at
4-6 years of age in US. In the current study, 81.6% had received 2nd
dose at 4-6 years and those who have received three doses, 94.7%
were vaccinated at 18-24 years [1]. Since no reliable correlate of
protection for the mumps vaccine and disease is known, it would be
of paramount interest to know for how long a single dose of mumps
vaccine provides protection.
2. The authors have studied attack rates of mumps
among students based on both the number of previous doses of MMR
vaccine received and the time since the receipt of the last dose of
MMR vaccine. It is not clear whether the number of doses received
earlier had some impact on the protection or is it the time since
the last dose of MMR that only matters. Whether the number of memory
B-cells and long lasting plasma cells induced by the previous
dose(s) of vaccine have some impact on the durability of protection?
3. The issue of routine 3rd dose of MMR vaccine
is still unresolved. Whether the 3rd dose is meant only to offer
protection during ongoing outbreaks in colleges/universities or
should it be offered routinely at appropriate interval to all 2-dose
recipients?
4. Whether different strains of mumps antigens
used in different MMR products have different impact on durability
of vaccine-induced immunity, a phenomenon referred commonly to as
‘immune escape’.
5. In the above study, 77 children have received
more than 3 doses of MMR vaccine. Was there any undesirable effect
of too many doses of MMR vaccine observed in any vaccinee?
What are the implications for India?
There are some significant differences in the
epidemiology of mumps disease and vaccination practices in US and India.
Hence, before analyzing any implication of the findings of the study for
us, let’s first enumerate some peculiar differences in US and Indian
scenario.
1. Mumps vaccination is not part of India’s UIP
despite a significant burden. Only private sector and few smaller
states are providing MMR vaccine to children and adolescents. There
are no data regarding the coverage of MMR vaccine in the target
population;
2. There is no surveillance system to
measure/monitor mumps disease in different age groups;
3. A different vaccination schedule of MMR is
used in private sector in India than in US where three doses of MMR
are given at 9 moths, 15 months, and 4-6 years of age [4].
4. A different mumps antigen (Leningrad-Zagreb)
is employed in the most widely used MMR vaccine formulation in India
than in US (Jeryl Lynn).
5. In India, the wild mumps virus is still widely
prevalent with opportunity of frequent natural boosting in different
age groups.
As per the data provided by IDSP and IDsurv, the
majority of mumps cases in India occur in more than 5 years of age [2].
There is no information regarding the extent of mumps outbreaks among
college-going students. The coverage of MMR vaccine among this group is
also not known, but believed to be miniscule. So, in Indian scenario,
the 3rd MMR dose used in US would be equivalent to 4th MMR dose if we go
by the IAP immunization schedule [4].
Coming back to the implications for India, first of
all, we must stop neglecting mumps disease. It is indeed a serious
public health concern [4,5]. The government should establish a
surveillance system to monitor/measure mumps cases. At least two doses
of MMR vaccine must be introduced in the UIP in place of Measles-Rubella
(MR) vaccine. According to WHO, two doses of the MMR vaccine are
sufficient to provide long-term protection against mumps [6]. Even in
US, the two-dose schedule has led to a 99% decrease in the incidence of
mumps in comparison to pre-vaccine period. Ironically, for the current
scenario of frequent outbreaks in college students in many developing
countries, the highly successful vaccination programs are to be blamed
since there are very little opportunities for sub-clinical natural
boosting. There is a need of rescheduling the MMR vaccination schedule
for private sector and an adolescent dose of mumps-containing vaccine
should be provided to adolescent/pre-adolescent children. Development of
a more potent mumps antigen with new formulations like mono- or bi-valent
products is also urgently needed.
Funding: None; Competing interests: None
stated.
Vipin M Vashishtha
Consultant Pediatrician,
Mangla Hospital and Research Center,
Bijnor,UP, India.
Email: [email protected]
References
1. Cardemil CV, Dahl RM, James L, Wannemuehler K,
Gary HE, Shah M, et al. Effectiveness of a third dose of MMR
vaccine for mumps outbreak control. N Engl J Med. 2017;377:947-56.
2. Vashishtha VM, Yadav S, Dabas A, Bansal CP,
Agarwal RC, Yewale VN, et al. IAP position paper on burden of
mumps in India and vaccination strategies. Indian Pediatr. 2015;
52:505-14.
3. Jenco M, ACIP: Give 3rd mumps vaccine dose during
outbreaks, AAP News, October 26, 2017. Available from:
http://www.aappublications.org/news/2017/10/26/Mumps102617. Accessed
November 14, 2017.
4. IAP Immunization Timetable 2016. Available from:
http://www.iapindia.org/page.php?id=129. Accessed November 14,
2017.
5. Vaidya SR, Hamde VS. Is it right time to introduce
mumps vaccine in India’s Universal Immunization Program? Indian Pediatr.
2016;53:469-73.
6. World Health Organization. Position Paper. Mumps
virus vaccines. Wkly Epidemiol Rec. 2007;7:51-60.
Virologist’s
Viewpoint
The robustness of an immune response after the
completion of primary immunization at stated dose and interval loses its
verve with the passing of time. Sustained protection is maintained by
periodic boosters of vaccines in many diseases, including poliomyelitis,
hepatitis B, whooping cough and tetanus. It is not yet fully understood
why some vaccines such as hepatitis A and B are effective for a fairly
prolonged period, and others require boosters. One view is if the immune
system responds rather rapidly to primary vaccine dose, the time gap
available for the body is rather insufficient to develop adequate memory
response resulting in low level persistence of memory cells in germinal
centers. Route of administration and quantum of dose influence the
outcome in some instances [1]. Natural immunity in general is longer
lasting than vaccine-induced immunity. The risks of natural infection
far outweigh the risks of immunization for every recommended vaccine. In
this observational study, Cardemil, et al. [2] reported their
observations on a mumps outbreak in adult student population of a
university in the US where proof of vaccination is mandatory for
enrolment as student and two doses MMR vaccine coverage exceeds 90%.
Waning of vaccine-induced protection, effectiveness of two-dose regimen
at 66-95% for mumps, and accumulation of susceptible hosts forgather
resulting in increased risk of exposure and intense respiratory
transmission of the virus. A difference in sero-response to measles
component of MMR vaccine has been documented, and a second dose restored
protective levels of antibody response. Host, agent and ethnic factors
may account for such differences [3]. The seminal findings of the
present report are:
1. Mumps attack rate is lower in recipients of
three doses of MMR.
2. Third dose of MMR improved mumps outbreak
control.
3. Risk of mumps is higher in vaccines who had
received second dose 13 years or earlier.
4. Vaccine effectiveness of two doses versus
no doses was lower among students who had received the second dose
in the distant past, enlisting waning protection.
Government of India’s decision to remove the mumps
component from MMR in its Universal Immunization Program is not
supported by Indian Academy of Pediatrics & Advisory Committee on
Vaccination & Immunization Practices [4]. Any momentous decision should
perhaps be effectuated after a careful analysis of disease burden and
ancillary consequences. The touchstones that need to be examined are: (i)
Is mumps a cause of significant burden? (ii) Is immunization an
optimal and desirable means of reducing disease burden? (iii) In
the absence of immuni-zation, can mumps be controlled? (iv) Are
there any unique operational problems in mumps immunization? The answer
to first two questions is "YES" and the other two, "NO."
Though usually mild in its presentation, many
patients may present with serious complications like aseptic meningitis
and encephalitis, resulting in disability or death. Permanent deafness,
orchitis, and pancreatitis are other untoward effects of mumps, besides
its purported role in Type1 diabetesmMellitus. Further, of the 12
genotypes of the virus, Genotype C and D circulating in Sweden are said
to be more neuropathogenic than genotype A. An association with CNS
disease was also found for the Odate-1 strain which is isolated in Japan
and sub-clusters within the genotypes C and H. Prudence demands a review
of the decision to withdraw mumps component from MMR for Indian
children. Beneficent elements of this study can be purposefully adopted
for instituting health management policy, after a scrutiny of the
following findings of the NEJM report:
1. Protective immunity wanes with time and
boosters are necessary to sustain durable protection.
2. In the absence of augmented immunization,
vulnerability to infection sets in and virus targets such population
with ease thereby initiating and propagating an outbreak.
3. MMR is useful in outbreak control.
Factoring the cost of a susceptible adult population
that may have escaped infection during childhood to fresh mumps attack
with its attendant complications in a growing economy needs
consideration while designing a region-specific health management
system.
Funding: None; Competing interests: The
author had been a Consultant – IAP Advisory Committee on vaccination and
Immunization practices (ACVIP) of Indian Academy of Pediatrics: January,
2013- December, 2014.
VG Ramachandran
Department of Microbiology, UCMS,
Delhi, India.
Email: [email protected]
References
1. Gomber S, Sharma R, Ramachandran VG.
Immunogenicity of low dose intradermal hepatitis B vaccine and its
comparison with standard dose intramuscular vaccination. Indian Pediatr.
2004;41:922-6.
2. Cardemil CV, Dahl RM, James L, Wannemuehler K,
Gary HE, Shah M, et al. Effectiveness of a third dose of MMR
vaccine for mumps outbreak control. N Engl J Med. 2017;377:947-56.
3. Gomber S, Arora SK, Das S, Ramachandran VG. Immune
response to second dose of MMR vaccine in Indian children. Indian J Med
Res 2011;134:302-6.
4. Vashishtha VM, Yadav S, Dabas A, Bansal CP, Agarwal RC, Yewale VN,
et al. IAP position paper on burden of Mumps in India and
vaccination strategies. Indian Pediatr. 2015;52:505-14.
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