MMR vaccine

MMR vaccine
Combination of
Measles vaccine Vaccine
Mumps vaccine Vaccine
Rubella vaccine Vaccine
Clinical data
ATC code J07BD52 (WHO)
Legal status
Legal status
  • ℞ (Prescription only)
Identifiers
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The MMR vaccine (also known as the MPR-vaccine after the Latin names of the diseases) is an immunization vaccine against measles, mumps, and rubella (German measles). It is a mixture of live attenuated viruses of the three diseases, administered via injection. It was first developed by Maurice Hilleman while at Merck.[1]

A licensed vaccine to prevent measles first became available in 1963, and an improved one in 1968. Vaccines for mumps and rubella became available in 1967 and 1969, respectively. The three vaccines (for mumps, measles, and rubella) were combined in 1971 to become the measles-mumps-rubella (MMR) vaccine.[2]

The MMR vaccine is generally administered to children around the age of one year, with a second dose before starting school (i.e. age 4/5). The second dose is a dose to produce immunity in the small number of persons (2–5%) who fail to develop measles immunity after the first dose.[3] In the United States, the vaccine was licensed in 1971 and the second dose was introduced in 1989.[4] It is widely used around the world; since introduction of its earliest versions in the 1970s, over 500 million doses have been used in over 60 countries. The vaccine is sold by Merck as M-M-R II, GlaxoSmithKline Biologicals as Priorix, Serum Institute of India as Tresivac, and Sanofi Pasteur as Trimovax.

It is usually considered a childhood vaccination. However, it is also recommended for use in some cases of adults with HIV.[5][6]

Maurice Hilleman

Effectiveness

Measles cases 1944-1963 followed a highly variable epidemic pattern, with 150,000-850,000 cases reported per year. A sharp decline followed introduction of the first measles vaccine in 1963, with fewer than 25,000 cases reported in 1968. Outbreaks around 1971 and 1977 gave 75,000 and 57,000 cases, respectively. Cases were stable at a few thousand per year until an outbreak of 28,000 in 1990. Cases declined from a few hundred per year in the early 1990s to a few dozen in the 2000s.
Measles cases reported in the United States fell dramatically after introduction of the measles vaccine.

Before the widespread use of a vaccine against measles, its incidence was so high that infection with measles was felt to be "as inevitable as death and taxes."[7] Reported cases of measles in the United States fell from hundreds of thousands to tens of thousands per year following introduction of the vaccine in 1963. Increasing uptake of the vaccine following outbreaks in 1971 and 1977 brought this down to thousands of cases per year in the 1980s. An outbreak of almost 30,000 cases in 1990 led to a renewed push for vaccination and the addition of a second vaccine to the recommended schedule. Fewer than 200 cases have been reported each year between 1997 and 2013, and the disease is no longer considered endemic.[8][9][10]

The benefit of measles vaccination in preventing illness, disability, and death has been well documented. The first 20 years of licensed measles vaccination in the U.S. prevented an estimated 52 million cases of the disease, 17,400 cases of intellectual disability, and 5,200 deaths.[11] During 1999–2004, a strategy led by the World Health Organization and UNICEF led to improvements in measles vaccination coverage that averted an estimated 1.4 million measles deaths worldwide.[12] Between 2000 and 2013, measles vaccination resulted in a 75% decrease in deaths from the disease.[13]

Measles is endemic worldwide. Although it was declared eliminated from the U.S. in 2000, high rates of vaccination and good communication with persons who refuse vaccination are needed to prevent outbreaks and sustain the elimination of measles in the U.S.[14] Of the 66 cases of measles reported in the U.S. in 2005, slightly over half were attributable to one unvaccinated individual who acquired measles during a visit to Romania.[15] This individual returned to a community with many unvaccinated children. The resulting outbreak infected 34 people, mostly children and virtually all unvaccinated; 9% were hospitalized, and the cost of containing the outbreak was estimated at $167,685. A major epidemic was averted due to high rates of vaccination in the surrounding communities.[14]

Mumps is another viral disease of childhood that was once very common. If mumps is acquired by a male who is past puberty, a possible complication is bilateral orchitis which can in some cases lead to sterility.[16]

Rubella fell sharply when immunization was introduced.

Rubella, otherwise known as German measles, was also very common before the advent of widespread vaccination. The major risk of rubella is in pregnancy. If a pregnant woman is infected, her baby may contract congenital rubella from her, which can cause significant congenital defects.[17]

The combined MMR vaccine was introduced to induce immunity less painfully than three separate injections at the same time, and sooner and more efficiently than three injections given on different dates.

In 2012, the Cochrane Library published a systematic review of scientific studies. Its authors concluded, "Existing evidence on the safety and effectiveness of MMR vaccine supports current policies of mass immunisation aimed at global measles eradication and in order to reduce morbidity and mortality associated with mumps and rubella."[18]

As measles and rubella cause upper respiratory disease that leads to complications of pneumonia and bronchitis which are also caused by varicella, MMR vaccine is beneficial to control exacerbations of chronic obstructive pulmonary disease (COPD) and asthma.

Development, formulation and administration

Two workers make openings in chicken eggs in preparation for a measles vaccine

The component viral strains of MMR vaccine were developed by propagation in animal and human cells. The live viruses require animal or human cells as a host for production of more virus.

For example, in the case of mumps and measles viruses, the virus strains were grown in embryonated hens' eggs and chick embryo cell cultures. This produced strains of virus which were adapted for the hens egg and less well-suited for human cells. These strains are therefore called attenuated strains. They are sometimes referred to as neuroattenuated because these strains are less virulent to human neurons than the wild strains.

The Rubella component, Meruvax, was developed in 1967 through propagation using the human embryonic lung cell line WI-38 (named for the Wistar Institute) that was derived 6 years earlier in 1961.[19][20]

Disease Immunized Component Vaccine Virus Strain Propagation Medium Growth Medium
Measles Attenuvax Enders' attenuated Edmonston strain[21] chick embryo cell culture Medium 199
Mumps Mumpsvax[22] Jeryl Lynn (B level) strain[23]
Rubella Meruvax II Wistar RA 27/3 strain of live attenuated rubella virus WI-38 human diploid lung fibroblasts MEM (solution containing buffered salts, fetal bovine serum, human serum albumin and neomycin, etc.)

MMR II is supplied freeze-dried (lyophilized) and contains live viruses. Before injection it is reconstituted with the solvent provided.

The MMR vaccine is administered by a subcutaneous injection.The second dose may be given as early as one month after the first dose.[24] The second dose is a dose to produce immunity in the small number of persons (2–5%) who fail to develop measles immunity after the first dose. In the U.S. it is done before entry to kindergarten because that is a convenient time.[3]

Safety

Adverse reactions, rarely serious, may occur from each component of the MMR vaccine. Ten percent of children develop fever, malaise, and a rash 5–21 days after the first vaccination;[25] and 3% develop joint pain lasting 18 days on average.[26] Older women appear to be more at risk of joint pain, acute arthritis, and even (rarely) chronic arthritis.[27] Anaphylaxis is an extremely rare but serious allergic reaction to the vaccine.[28] One cause can be egg allergy.[29] In 2014, the FDA approved two additional possible adverse events on the vaccination label for ADEM (acute disseminated encephalomyelitis), and transverse myelitis, with permission to also add "difficulty walking" to the package inserts.[30]

The number of reports on neurological disorders is very small, other than evidence for an association between a form of the MMR vaccine containing the Urabe mumps strain and rare adverse events of aseptic meningitis, a transient mild form of viral meningitis.[27][31] The UK National Health Service stopped using the Urabe mumps strain in the early 1990s due to cases of transient mild viral meningitis, and switched to a form using the Jeryl Lynn mumps strain instead.[32] The Urabe strain remains in use in a number of countries; MMR with the Urabe strain is much cheaper to manufacture than with the Jeryl Lynn strain,[33] and a strain with higher efficacy along with a somewhat higher rate of mild side effects may still have the advantage of reduced incidence of overall adverse events.[32]

The Cochrane Library review found that, compared with placebo, MMR vaccine was associated with fewer upper respiratory tract infections, more irritability, and a similar number of other adverse effects.[18]

Naturally acquired measles often occurs with idiopathic thrombocytopenic purpura (ITP, a purpuric rash and an increased tendency to bleed that resolves within two months in children). Between 1 in 25,000 and 1 in 40,000 children are thought to acquire ITP in the six weeks following an MMR vaccination, which is a higher rate than found in unvaccinated populations. ITP below the age of 6 years is generally a mild disease, rarely having long-term consequences.[34][35]

Claims about autism

In 1998 Andrew Wakefield et al. published a fraudulent paper about twelve children, reportedly with bowel symptoms and autism, or other disorders soon after administration of MMR vaccine.[36] In 2010, Wakefield's research was found by the General Medical Council to have been "dishonest",[37] and The Lancet fully retracted the paper.[38] Three months following The Lancet's retraction, Wakefield was struck off the UK medical register, with a statement identifying deliberate falsification in the research published in The Lancet,[39] and was barred from practising medicine in the UK.[40] The research was declared fraudulent in 2011 by the British Medical Journal.[41]

Many peer-reviewed studies have failed to show any association between the vaccine and autism.[42] The Centers for Disease Control and Prevention,[43] the Institute of Medicine of the National Academy of Sciences,[44] the UK National Health Service[45] and the Cochrane Library review[18] have all concluded that there is no evidence of a link.

Administering the vaccines in three separate doses does not reduce the chance of adverse effects, and it increases the opportunity for infection by the two diseases not immunized against first.[42][46] Health experts have criticized media reporting of the MMR-autism controversy for triggering a decline in vaccination rates.[47] Before publication of Wakefield's findings, the inoculation rate for MMR in the UK was 92%; after publication, the rate dropped to below 80%. In 1998, there were 56 measles cases in the UK; by 2008, there were 1348 cases, with two confirmed deaths.[48]

In Japan, the MMR vaccination has been discontinued, with single vaccines being used for each disease (or in practice the vaccines are given as two doses. One a combination vaccine for Measles and Rubella MR and the other Mumps vaccine being given as a single dose). Rates of autism diagnosis have continued to increase, showing no correlation with the change.[49]

In the United States, a number of celebrities have become anti-vaccination spokespeople. These include actors Jenny McCarthy,[50] and Jim Carrey,[51] as well as President Elect of the United States Donald Trump.[52]

MMRV vaccine

Main article: MMRV vaccine

The MMRV vaccine, a combined measles, mumps, rubella and varicella vaccine, has been proposed as a replacement for the MMR vaccine to simplify administration of the vaccines.[24] Preliminary data indicate a rate of fever fits of 9 per 10,000 vaccinations with MMRV, as opposed to 4 per 10,000 for separate MMR and varicella shots; U.S. health officials therefore do not express a preference for use of MMRV vaccine over separate injections.[53]

In a 2012 study[54] pediatricians and family doctors were sent a survey to gauge their awareness of the increased risk of febrile seizures (fever fits) in the MMRV. 74% of family doctors and 29% of pediatricians were unaware of the increased risk of febrile seizures. After reading an informational statement only 7% of family doctors and 20% of pediatricians would recommend the MMRV for a healthy 12- to 15-month-old child. The factor that was reported as the "most important" deciding factor in recommending the MMRV over the MMR+V was ACIP/AAFP/AAP recommendations (pediatricians, 77%; family physicians, 73%).

References

  1. ↑ Offit PA (2007). Vaccinated: One Man's Quest to Defeat the World's Deadliest Diseases. Washington, DC: Smithsonian. ISBN 0-06-122796-X.
  2. ↑ Measles: Questions and Answers, Immunization Action Coalition.
  3. 1 2 "MMR vaccine questions and answers". Centers for Disease Control and Prevention. 2004. Archived from the original on July 25, 2008. Retrieved 2008-05-28.
  4. ↑ Banatvala JE, Brown DW (2004). "Rubella". Lancet. 363 (9415): 1127–37. doi:10.1016/S0140-6736(04)15897-2. PMID 15064032.
  5. ↑ "Case 4: Discussion - Appropriate Vaccinations - Initial Evaluation - HIV Web Study".
  6. ↑ "Measles, Mumps, and Rubella -- Vaccine Use and Strategies for Elimination of Measles, Rubella, and Congenital Rubella Syndrome and Control of Mumps: Recommendations of the Advisory Committee on Immunization Practices (ACIP)".
  7. ↑ Babbott FL Jr; Gordon JE (1954). "Modern measles". Am J Med Sci. 228 (3): 334–61. PMID 13197385.
  8. ↑ Centers for Disease Control and Prevention Summary of notifable diseases—United States, 1993 Published October 21, 1994 for Morbidity and Mortality Weekly Report 1993; 42 (No. 53)
  9. ↑ Centers for Disease Control and Prevention Summary of notifable diseases—United States, 2007 Published July 9, 2009 for Morbidity and Mortality Weekly Report 2007; 56 (No. 53)
  10. ↑ Centers for Disease Control and Prevention. Epidemiology and Prevention of Vaccine-Preventable Diseases. Atkinson W, Wolfe S, Hamborsky J, McIntyre L, eds. 11th ed. Washington DC: Public Health Foundation, 2009
  11. ↑ Bloch AB, Orenstein WA, Stetler HC, et al. (1985). "Health impact of measles vaccination in the United States". Pediatrics. 76 (4): 524–32. PMID 3931045.
  12. ↑ Centers for Disease Control and Prevention (CDC) (2006). "Progress in reducing global measles deaths, 1999–2004". MMWR Morb Mortal Wkly Rep. 55 (9): 247–9. PMID 16528234.
  13. ↑ "Measles Fact Sheet #286". World Health Organization. Retrieved 1 December 2014.
  14. 1 2 Parker AA, Staggs W, Dayan GH, et al. (2006). "Implications of a 2005 measles outbreak in Indiana for sustained elimination of measles in the United States". N Engl J Med. 355 (5): 447–55. doi:10.1056/NEJMoa060775. PMID 16885548.
  15. ↑ Centers for Disease Control and Prevention (CDC) (2006). "Measles—United States, 2005". MMWR Morb Mortal Wkly Rep. 55 (50): 1348–51. PMID 17183226.
  16. ↑ Jequier, Anne M. (2000). Male infertility: a guide for the clinician. Malden, MA: Blackwell Publishing. p. 118. ISBN 0-632-05129-9.
  17. ↑ "Rubella vaccine information". National Network for Immunization Information. 2006-09-25. Retrieved 2007-09-02.
  18. 1 2 3 Demicheli V, Rivetti A, Debalini MG, Di Pietrantonj C (2012). "Vaccines for measles, mumps and rubella in children". Cochrane Database Syst Rev. 2: CD004407. doi:10.1002/14651858.CD004407.pub3. PMID 22336803.
  19. ↑ Plotkin SA, Vaheri A (1967). "Human fibroblasts infected with rubella virus produce a growth inhibitor. Science. 1967 May 5;156(3775):659-61.". Retrieved 2015-05-01.
  20. ↑ Hayflick L, Moorhead PS (1967). "The serial cultivation of human diploid cell strains. Exp Cell Res. 1961 Dec;25:585-621.". Retrieved 2015-05-01.
  21. ↑ "Attenuvax Product Sheet" (PDF). Merck & Co. 2006. p. 1. Archived from the original (PDF) on 2009-12-31. Retrieved 2009-02-04.
  22. ↑ Merck Co. (2002). "MUMPSVAX (Mumps Virus Vaccine Live) Jeryl Lynn Strain" (PDF). Merck Co. Archived from the original (PDF) on 2006-08-13. Retrieved 2015-01-26.
  23. ↑ Young ML, Dickstein B, Weibel RE, Stokes J Jr, Buynak EB, Hilleman MR (1967). "Experiences with Jeryl Lynn strain live attenuated mumps virus vaccine in a pediatric outpatient clinic". Pediatrics. 40 (5): 798–803. PMID 6075651.
  24. 1 2 Vesikari T, Sadzot-Delvaux C, Rentier B, Gershon A (2007). "Increasing coverage and efficiency of measles, mumps, and rubella vaccine and introducing universal varicella vaccination in Europe: a role for the combined vaccine". Pediatr Infect Dis J. 26 (7): 632–8. doi:10.1097/INF.0b013e3180616c8f. PMID 17596807.
  25. ↑ Harnden A, Shakespeare J (2001). "10-minute consultation: MMR immunisation". BMJ. 323 (7303): 32. doi:10.1136/bmj.323.7303.32. PMC 1120664Freely accessible. PMID 11440943.
  26. ↑ Thompson GR, Ferreyra A, Brackett RG (1971). "Acute Arthritis Complicating Rubella Vaccination". Arthritis & Rheumatism. 14 (1): 19–26. doi:10.1002/art.1780140104.
  27. 1 2 Schattner A (2005). "Consequence or coincidence? The occurrence, pathogenesis and significance of autoimmune manifestations after viral vaccines". Vaccine. 23 (30): 3876–86. doi:10.1016/j.vaccine.2005.03.005. PMID 15917108.
  28. ↑ Carapetis JR, Curtis N, Royle J (2001). "MMR immunisation. True anaphylaxis to MMR vaccine is extremely rare". BMJ. 323 (7317): 869. doi:10.1136/bmj.323.7317.869a. PMC 1121404Freely accessible. PMID 11683165.
  29. ↑ Fox A, Lack G (October 2003). "Egg allergy and MMR vaccination". Br J Gen Pract. 53 (495): 801–2. PMC 1314715Freely accessible. PMID 14601358.
  30. ↑ "Approval for label change".
  31. ↑ Institute of Medicine (1994). "Measles and mumps vaccines". Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality. National Academy Press. ISBN 0-309-07496-7.
  32. 1 2 Colville A, Pugh S, Miller E, Schmitt HJ, Just M, Neiss A (1994). "Withdrawal of a mumps vaccine". Eur J Pediatr. 153 (6): 467–8. doi:10.1007/BF01983415. PMID 8088305.
  33. ↑ Fullerton KE, Reef SE (2002). "Commentary: Ongoing debate over the safety of the different mumps vaccine strains impacts mumps disease control". Int J Epidemiol. 31 (5): 983–4. doi:10.1093/ije/31.5.983. PMID 12435772.
  34. ↑ Sauvé LJ, Scheifele D (January 2009). "Do childhood vaccines cause thrombocytopenia?". Paediatr Child Health. 14 (1): 31–2. PMC 2661332Freely accessible. PMID 19436461.
  35. ↑ Black, C., Kaye, J. A. and Jick, H. (2003). "MMR vaccine and idiopathic thrombocytopaenic purpura". British Journal of Clinical Pharmacology. 55 (1): 107–111. doi:10.1046/j.1365-2125.2003.01790.x. PMC 1884189Freely accessible. PMID 12534647.
  36. ↑ Wakefield A, Murch S, Anthony A; et al. (1998). "Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children". Lancet. 351 (9103): 637–41. doi:10.1016/S0140-6736(97)11096-0. PMID 9500320. Retrieved 2007-09-05. (Retracted)
  37. ↑ Cassandra Jardine (29 Jan 2010). "GMC brands Dr Andrew Wakefield 'dishonest, irresponsible and callous'". The Telegraph. London: Telegraph Media Group, Ltd. Retrieved 31 January 2015.
  38. ↑ The Editors Of The Lancet (February 2010). "Retraction—Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children". Lancet. 375 (9713): 445. doi:10.1016/S0140-6736(10)60175-4. PMID 20137807. Lay summary – BBC News (2010-02-02).
  39. ↑ "General Medical Council, Fitness to Practise Panel Hearing, 24 May 2010, Andrew Wakefield, Determination of Serious Professional Misconduct" (PDF). General Medical Council. Archived from the original (PDF) on 9 August 2011. Retrieved 18 September 2011.
  40. ↑ Meikle, James; Boseley, Sarah (24 May 2010). "MMR row doctor Andrew Wakefield struck off register". The Guardian. London. Archived from the original on 27 May 2010. Retrieved 24 May 2010.
  41. ↑ Godlee F, Smith J, Marcovitch H (2011). "Wakefield's article linking MMR vaccine and autism was fraudulent". BMJ. 342:c7452 (jan05 1): c7452–c7452. doi:10.1136/bmj.c7452. PMID 21209060.
  42. 1 2 National Health Service (2004). "MMR: myths and truths". Retrieved 2007-09-03.
  43. ↑ "Measles, mumps, and rubella (MMR) vaccine". Centers for Disease Control and Prevention. 2008-08-22. Archived from the original on 2008-10-08. Retrieved 2008-12-21.
  44. ↑ Immunization Safety Review: Vaccines and Autism. From the Institute of Medicine of the National Academy of Sciences. Report dated May 17, 2004; accessed June 13, 2007.
  45. ↑ MMR Fact Sheet, from the United Kingdom National Health Service. Accessed June 13, 2007.
  46. ↑ MMR vs three separate vaccines:
  47. ↑ "Doctors issue plea over MMR jab". BBC News. 2006-06-26. Retrieved 2009-02-04.
  48. ↑ Thomas J (2010). "Paranoia strikes deep: MMR vaccine and autism". Psychiatric Times. 27 (3): 1–6.
  49. ↑ Honda H, Shimizu Y, Rutter M (2005). "No effect of MMR withdrawal on the incidence of autism: a total population study". J Child Psychol Psychiatry. 46 (6): 572–9. doi:10.1111/j.1469-7610.2005.01425.x. PMID 15877763. Lay summary – Bandolier (2005).
  50. ↑ "Jenny McCarthy: anti-vaxxer, public menace". Los Angeles Times. 2015-01-27.
  51. ↑ "The Judgment on Vaccines Is In???". Huffington Post. 2009-04-22.
  52. ↑ "Why Does Donald Trump Think Vaccines Cause Autism?". Huffington Post. 2012-04-13.
  53. ↑ Klein NP, Yih WK, Marin M, et al. (2008). "Update: recommendations from the Advisory Committee on Immunization Practices (ACIP) regarding administration of combination MMRV vaccine". MMWR Morb Mortal Wkly Rep. 57 (10): 258–60. PMID 18340332.
  54. ↑ "Febrile seizures and measles-mumps-rubella-varicella (MMRV) vaccine: what do primary care physicians think?". Vaccine. 30 (48): 6731–3. Nov 2012. doi:10.1016/j.vaccine.2012.08.075. PMID 22975026.
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