An increasing number of cases of POI post-HPV4 are being reported. Possible mechanisms for the suspected effect of HPV on female reproductive function are a toxic effect or an autoimmune response. The trigger could be the vaccine immunogen contents or the adjuvants, the latter are used to increase the immune reaction. The adjuvant in HPV4 contains aluminum. Animal models have shown aluminum exposure to inhibit expression of female reproductive hormones and to induce histologic changes in the ovaries. Specific genetic compositions may be more susceptible to developing an autoinflammatory syndrome after exposure to an environmental factor.

 

Little, Deirdre Therese, and Harvey Rodrick Grenville Ward. "Adolescent premature ovarian insufficiency following human papillomavirus vaccination: a case series seen in general practice." Journal of investigative medicine high impact case reports 2, no. 4 (2014): 2324709614556129.

 

Abstract 

Three young women who developed premature ovarian insufficiency following quadrivalent human papillomavirus (HPV) vaccination presented to a general practitioner in rural New South Wales, Australia. The unrelated girls were aged 16, 16, and 18 years at diagnosis. Each had received HPV vaccinations prior to the onset of ovarian decline. Vaccinations had been administered in different regions of the state of New South Wales and the 3 girls lived in different towns in that state. Each had been prescribed the oral contraceptive pill to treat menstrual cycle abnormalities prior to investigation and diagnosis. Vaccine research does not present an ovary histology report of tested rats but does present a testicular histology report. Enduring ovarian capacity and duration of function following vaccination is unresearched in preclinical studies, clinical and post-licensure studies. Post marketing surveillance does not accurately represent diagnoses in adverse event notifications and can neither represent unnotified cases nor compare incident statistics with vaccine course administration rates. The potential significance of a case series of adolescents with idiopathic premature ovarian insufficiency following HPV vaccination presenting to a general practice warrants further research. Preservation of reproductive health is a primary concern in the recipient target group. Since this group includes all prepubertal and pubertal young women, demonstration of ongoing, uncompromised safety for the ovary is urgently required. This matter needs to be resolved for the purposes of population health and public vaccine confidence.

 

Little, Deirdre Therese, and Harvey Rodrick Grenville Ward. "Premature ovarian failure 3 years after menarche in a 16-year-old girl following human papillomavirus vaccination." Case Reports 2012 (2012): bcr2012006879.

 

Summary

Premature ovarian failure in a well adolescent is a rare event. Its occurrence raises important questions about causation, which may signal other systemic concerns. This patient presented with amenorrhoea after identifying a change from her regular cycle to irregular and scant periods following vaccinations against human papillomavirus. She declined the oral contraceptives initially prescribed for amenorrhoea. The diagnostic tasks were to determine the reason for her secondary amenorrhoea and then to investigate for possible causes of the premature ovarian failure identified. Although the cause is unknown in 90% of cases, the remaining chief identifiable causes of this condition were excluded. Premature ovarian failure was then notified as a possible adverse event following this vaccination. The young woman was counselled regarding preservation of bone density, reproductive implications and relevant follow-up. This event could hold potential implications for population health and prompts further inquiry

Pellegrino, Paolo, Carla Carnovale, Valentina Perrone, Dionigi Salvati, Marta Gentili, Tatiana Brusadelli, Marco Pozzi, Stefania Antoniazzi, Emilio Clementi, and Sonia Radice. "On the association between human papillomavirus vaccine and primary ovarian failure." American Journal of Reproductive Immunology 71, no. 4 (2014): 293-294.

 

Tomljenovic, Lucija, and Christopher A. Shaw. "Adverse reactions to human papillomavirus vaccines." Vaccines and Autoimmunity (2015): 163-174.

 

Summary

This chapter reviews the data from numerous reports substantiating the link between adverse immune reactions and human papillomavirus (HPV) vaccines. It discusses the results from safety clinical trials on HPV vaccines. In their 2008 pre‐licensure analysis of ADRs of potential autoimmune etiology in a large integrated safety database of ASO4 adjuvanted vaccines (including Cervarix), Verstraeten et al. pointed out that “It is important to note that none of these studies were set up primarily to study autoimmune disorders.” Large post‐licensure epidemiological studies assessing the safety of Gardasil likewise failed to identify any significant autoimmune safety concerns. Post‐vaccination adverse immune phenomena can have long latency periods. The human clinical trial data for the two HPV vaccines currently on the market reveal a troubling safety profile that requires an accurate reevaluation of the risks and benefits.

 

Tomljenovic, Lucija, and C. A. Shaw. "Death after quadrivalent human papillomavirus (HPV) vaccination: causal or coincidental." Pharmaceut Reg Affairs S 12 (2012): 2.

 

Abstract:

Background: The proper understanding of a true risk from vaccines is crucial for avoiding unnecessary adverse reactions (ADRs). However, to this date no solid tests or criteria have been established to determine whether adverse events are causally linked to vaccinations. 

Objectives: This research was carried out to determine whether or not some serious autoimmune and neurological ADRs following HPV vaccination are causal or merely coincidental and to validate a biomarker-based immunohistochemical (IHC) protocol for assessing causality in case of vaccination-suspected serious adverse neurological outcomes.

Methods: Post-mortem brain tissue specimens from two young women who suffered from cerebral vasculitis type symptoms following vaccination with the HPV vaccine Gardasil were analysed by IHC for various immunoinflammatory markers. Brain sections were also stained for antibodies recognizing HPV-16L1 and HPV-18L1 antigen which are present in Gardasil. Results: In both cases, the autopsy revealed no anatomical, microbiological nor toxicological findings that might have explained the death of the individuals. In contrast, our IHC analysis showed evidence of an autoimmune vasculitis potentially triggered by the cross-reactive HPV-16L1 antibodies binding to the wall of cerebral blood vessels in all examined brain samples. We also detected the presence of HPV-16L1 particles within the cerebral vasculature with some HPV-16L1 particles adhering to the blood vessel walls. HPV-18L1 antibodies did not bind to cerebral blood vessels nor any other neural tissues. IHC also showed increased T-cell signalling and marked activation of the classical antibody-dependent complement pathway in cerebral vascular tissues from both cases. This pattern of complement activation in the absence of an active brain infection indicates an abnormal triggering of the immune response in which the immune attack is directed towards self-tissue. 

Conclusions: Our study suggests that HPV vaccines containing HPV-16L1 antigens pose an inherent risk for triggering potentially fatal autoimmune vasculopathies. Practice implications: Cerebral vasculitis is a serious disease which typically results in fatal outcomes when undiagnosed and left untreated. The fact that many of the symptoms reported to vaccine safety surveillance databases following HPV vaccination are indicative of cerebral vasculitis, but are unrecognized as such (i.e., intense persistent migraines, syncope, seizures, tremors and tingling, myalgia, locomotor abnormalities, psychotic symptoms and cognitive deficits), is a serious concern in light of the present findings. It thus appears that in some cases vaccination may be the triggering factor of fatal autoimmune/neurological events. Physicians should be aware of this association

 

Tomljenovic, Lucija, Serena Colafrancesco, Carlo Perricone, and Yehuda Shoenfeld. "Postural orthostatic tachycardia with chronic fatigue after HPV vaccination as part of the “Autoimmune/Auto-inflammatory Syndrome Induced by Adjuvants” case report and literature review." Journal of investigative medicine high impact case reports 2, no. 1 (2014): 2324709614527812.

 

Abstract

We report the case of a 14-year-old girl who developed postural orthostatic tachycardia syndrome (POTS) with chronic fatigue 2 months following Gardasil vaccination. The patient suffered from persistent headaches, dizziness, recurrent syncope, poor motor coordination, weakness, fatigue, myalgias, numbness, tachycardia, dyspnea, visual disturbances, phonophobia, cognitive impairment, insomnia, gastrointestinal disturbances, and a weight loss of 20 pounds. The psychiatric evaluation ruled out the possibility that her symptoms were psychogenic or related to anxiety disorders. Furthermore, the patient tested positive for ANA (1:1280), lupus anticoagulant, and antiphospholipid. On clinical examination she presented livedo reticularis and was diagnosed with Raynaud’s syndrome. This case fulfills the criteria for the autoimmune/auto-inflammatory syndrome induced by adjuvants (ASIA). Because human papillomavirus vaccination is universally recommended to teenagers and because POTS frequently results in long-term disabilities (as was the case in our patient), a thorough follow-up of patients who present with relevant complaints after vaccination is strongly recommended.

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Tetanus Vaccine Description and Reactions

In the U.S. today, tetanus vaccine is administered only in a combination shot (DTaP, DT, Tdap, Td) that contains vaccines for tetanus (T), diphtheria (D) and possibly pertussis (whooping cough) (P). The CDC’s Advisory Committee on Immunization Practices (ACIP) currently recommends administration of a tetanus containing vaccine (DTaP) at two, four, and six months old; between 15 and 18 months old; and between four and six years old. Another booster dose is recommended at 11-12 years of age (Tdap). After a booster dose of Tdap vaccine, booster doses with tetanus - diphtheria toxoid vaccine (Td) are recommended every ten years throughout a person’s life. While the ACIP also recommends that pregnant women receive a dose of Tdap vaccine during each pregnancy, between 27- and 36-weeks gestation, regardless of a previous history of Tdap vaccine, this recommendation contradicts the information provided by the vaccine manufacturers. Boostrix vaccine is approved to be administered only as a single dose and the Adacel product insert states that a second dose of Adacel vaccine may be administered if there has been at least an 8-year interval between the first Tdap dose. The product insert of both Boostrix and Adacel, the two available FDA licensed Tdap vaccines, also state that there are “no adequate and well-controlled studies” on the use of Tdap vaccine in pregnant women. 

The tetanus toxoid vaccine (TT) was developed in 1924 and became commercially available for use in the United States in 1938. Prior to 1960, the tetanus toxoid (TT) was primarily used, however in the 1960’s, the use of the combination tetanus- diphtheria toxoid vaccine (Td) became more prevalent. In 2013, the single antigen tetanus toxoid vaccine (TT) was discontinued in the United States. The tetanus toxoid vaccine is available only in combination with other routinely administered vaccines and most frequently combined with diphtheria (DT, Td) and acellular pertussis vaccines (DTaP, Tdap). It can also be found in combination with vaccines for polio, haemophilus influenzae B (HIB), and hepatitis B (see below for descriptions).

 

Tetanus Toxoid Vaccines Licensed for Use in the U.S.

The U.S. FDA has approved twelve different combination vaccine that include tetanus toxoid vaccine. There are different rules for use of these vaccines by different aged groups.

Following is a list of currently available vaccine combination shots that contain tetanus toxoid vaccine with links to the manufacturer product inserts (click on the name of the product):

• Infanrix, a 3 in 1 combination shot containing diphtheria, tetanus toxoids, and acellular pertussis vaccine for children under 7 years of age. It is manufactured by GlaxoSmithKline.

• DAPTACEL, a 3 in 1 combination shot containing diphtheria and tetanus toxoids and acellular pertussis vaccine for children under 7 years of age. It is manufactured by Sanofi Pasteur Ltd.

• Pediarix, a 5 in 1 combination shot containing diphtheria and tetanus toxoids and acellular pertussis, hepatitis B recombinant and inactivated poliovirus vaccines for children under 7 years of age. It is manufactured by GlaxoSmithKline.

• Kinrix, a 4 in 1 combination vaccine containing diphtheria and tetanus toxoids, acellular pertussis, and inactivated poliovirus vaccines for children 4 to 6 years old. It is manufactured by GlaxoSmithKline.

• Quadracel, a 4 in 1 combination vaccine containing diphtheria and tetanus toxoid, acellular pertussis, and inactivated poliovirus vaccine for children 4 to 6 years old. It is manufactured by Sanofi Pasteur

• Pentacel, a 5 in 1 combination shot containing diphtheria and tetanus toxoids and acellular pertussis, inactivated poliovirus and Haemophilus b conjugate (tetanus toxoid conjugate) vaccine for children under four years old. It is manufactured by Sanofi Pasteur Ltd.

• VAXELIS, a 6 in 1 combination shot containing diphtheria and tetanus toxoids and acellular pertussis, inactivated poliovirus, Haemophilus b conjugate, and hepatitis B recombinant vaccine for children under 5 years of age. It is manufactured by MCM Vaccine Company. (Not currently available for use)

• Diphtheria and Tetanus Toxoid Adsorbed, a 2 in 1 combination shot containing diphtheria and tetanus toxoid for children under seven years old. It is manufactured by Sanofi Pasteur Ltd

• Adacel, a 3 in 1 combination booster shot containing tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine for those 10 years or older. It is manufactured by Sanofi Pasteur Ltd.

• Boostrix, a 3 in 1 combination booster shot containing tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine for those 10 years or older. It is manufactured by GlaxoSmithKline.

• TDVAX, a 2 in 1 combination shot containing tetanus and diphtheria toxoid for those 7 years of age or older. It is manufactured by MassBiologics

• TENIVAC, a 2 in 1 combination shot containing tetanus and diphtheria toxoid for those 7 years of age or older. It is manufactured by Sanofi Pasteur

 

Combination Vaccines

There are some doctors who limit the numbers of vaccines given simultaneously on the same day and will work as partners with parents to choose certain vaccine products and develop individualized schedules for vaccination. If you want your child to receive tetanus vaccine but would prefer a 3 in 1 combination shot (diphtheria, tetanus, and pertussis) rather than a 4 in 1 or 5 in 1 combination shot, talk with your doctor.

If your doctor or the nurse administering vaccines refuses to have a discussion with you about vaccine products or schedules, you may want to consider consulting one or more other trusted health care professionals before making a vaccine decision.

Not all tetanus-containing vaccines have been studied in clinical trials to prove the safety and effectiveness of giving the shot simultaneously with other licensed vaccines. Check the product inserts for more information about administering vaccines at the same time with other vaccines.

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Source: NVIC.ORG

Articles DPT Vaccine Reactions

Cody, Christopher L., Larry J. Baraff, James D. Cherry, S. Michael Marcy, and Charles R. Manclark. "Nature and rates of adverse reactions associated with DTP and DT immunizations in infants and children." Pediatrics 68, no. 5 (1981): 650-660.

 

Abstract

In 784 DT and 15,752 DTP immunizations given to children 0 to 6 years of age who were prospectively studied for reactions occurring within 48 hours following immunization, minor reactions were significantly more frequent following DTP vaccine. The ratio of reaction rates associated with DTP and DT immunizations (DTP/DT) for selected local and systemic reactions was as follows: local redness, 37.4%/7.6%; local swelling, 40.7%/7.6%; pain, 50.9%/9.9%; fever, 31.5%/14.9%; drowsiness, 31.5%/14.9%; fretfulness, 53.4%/22.6%; vomiting, 6.2%/2.6%; anorexia, 20.9%/7.0% and persistent crying, 3.1%/0.7%. Following DTP immunization nine children developed convulsions and nine developed hypotonic hyporesponsive episodes. No sequelae were detected following these reactions.

Sun, Yuelian, Jakob Christensen, Anders Hviid, Jiong Li, Peter Vedsted, Jørn Olsen, and Mogens Vestergaard. "Risk of febrile seizures and epilepsy after vaccination with diphtheria, tetanus, acellular pertussis, inactivated poliovirus, and Haemophilus influenzae type B." Jama 307, no. 8 (2012): 823-831.

 

Abstract

Context Vaccination with whole-cell pertussis vaccine carries an increased risk of febrile seizures, but whether this risk applies to the acellular pertussis vaccine is not known. In Denmark, acellular pertussis vaccine has been included in the combined diphtheria-tetanus toxoids-acellular pertussis–inactivated poliovirus– Haemophilus influenzae type b (DTaP-IPV-Hib) vaccine since September 2002.

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Objective To estimate the risk of febrile seizures and epilepsy after DTaP-IPV-Hib vaccination given at 3, 5, and 12 months.

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Design, Setting, and Participants A population-based cohort study of 378 834 children who were born in Denmark between January 1, 2003, and December 31, 2008, and followed up through December 31, 2009; and a self-controlled case series (SCCS) study based on children with febrile seizures during follow-up of the cohort.

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Main Outcome Measures Hazard ratio (HR) of febrile seizures within 0 to 7 days (0, 1-3, and 4-7 days) after each vaccination and HR of epilepsy after first vaccination in the cohort study. Relative incidence of febrile seizures within 0 to 7 days (0, 1-3, and 4-7 days) after each vaccination in the SCCS study.

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Results A total of 7811 children were diagnosed with febrile seizures before 18 months, of whom 17 were diagnosed within 0 to 7 days after the first (incidence rate, 0.8 per 100 000 person-days), 32 children after the second (1.3 per 100 000 person-days), and 201 children after the third (8.5 per 100 000 person-days) vaccinations. Overall, children did not have higher risks of febrile seizures during the 0 to 7 days after the 3 vaccinations vs a reference cohort of children who were not within 0 to 7 days of vaccination. However, a higher risk of febrile seizures was found on the day of the first (HR, 6.02; 95% CI, 2.86-12.65) and on the day of the second (HR, 3.94; 95% CI, 2.18-7.10), but not on the day of the third vaccination (HR, 1.07; 95% CI, 0.73-1.57) vs the reference cohort. On the day of vaccination, 9 children were diagnosed with febrile seizures after the first (5.5 per 100 000 person-days), 12 children after the second (5.7 per 100 000 person-days), and 27 children after the third (13.1 per 100 000 person-days) vaccinations. The relative incidences from the SCCS study design were similar to the cohort study design. Within 7 years of follow-up, 131 unvaccinated children and 2117 vaccinated children were diagnosed with epilepsy, 813 diagnosed between 3 and 15 months (2.4 per 1000 person-years) and 1304 diagnosed later in life (1.3 per 1000 person-years). After vaccination, children had a lower risk of epilepsy between 3 and 15 months (HR, 0.63; 95% CI, 0.50-0.79) and a similar risk for epilepsy later in life (HR, 1.01; 95% CI, 0.66-1.56) vs unvaccinated children.

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Conclusions DTaP-IPV-Hib vaccination was associated with an increased risk of febrile seizures on the day of the first 2 vaccinations given at 3 and 5 months, although the absolute risk was small. Vaccination with DTaP-IPV-Hib was not associated with an increased risk of epilepsy.

Studies have reported increased risks of febrile seizures shortly after administration of whole-cell pertussis vaccine, as would be expected since the whole-cell pertussis vaccine often causes fever. Whole-cell pertussis vaccine has also been associated with serious neurological illnesses characterized by seizures and intellectual impairment, but recent studies indicate that the vaccination only triggers an earlier onset of severe epileptic encephalopathy in children with sodium channel gene mutations. The acellular pertussis vaccine has replaced the whole-cell pertussis vaccine in most countries because the efficacy of the acellular vaccine is comparable with the whole-cell vaccine and it has substantially fewer adverse effects, including fever. Previous randomized controlled trials did not reveal differences in the risk of seizures after acellular pertussis vaccination compared with whole-cell pertussis vaccination, but the trials were not powered to detect rare adverse effects. A study from the United Kingdom found a 2-fold higher risk of seizures on the day of the diphtheria-tetanus toxoids-acellular pertussis–inactivated poliovirus– Haemophilus influenzae type b (DTaP-IPV-Hib) vaccination, and a study from the United States found a 30% higher risk of seizures on the day of the first DTaP vaccination. However, these estimates did not reach statistical significance and the studies did not distinguish between afebrile and febrile seizures. We examined the risk of febrile seizures and epilepsy after DTaP-IPV-Hib vaccination in a large nationwide, population-based cohort study in Denmark.

 

Measles, Mumps, Rubella Vaccine Description and Reactions

Measles vaccine is a weakened (attenuated) form of the live measles virus. There are 2 vaccines currently available for use in the U.S.: Merck's MMRII, which contains Measles, Mumps and Rubella Vaccine, Live; and Merck's Proquad (MMRV), which contains Measles, Mumps, Rubella and Varicella, Live.  

Merck’s MMRII is licensed and recommended for individuals aged 12 months or older. It is a live attenuated virus vaccine propagated in chick embryo cells and cultured with Jeryl Lynn live attenuated virus mumps and Meruvax II, a live attenuated rubella virus vaccine propagated in WI-38 human diploid lung fibroblasts. The WI-38 human diploid cell line was derived from the lung tissue of a three-month human female embryo. The growth medium used was salt solution and 10 percent calf (bovine) serum. 

Merck's ProQuad is licensed and recommended for individuals aged 12 months to 12 years of age. ProQuad (MMR-V -Measles, Mumps, Rubella and Varicella Virus Vaccine Live) is a combined, attenuated, live virus vaccine containing measles, mumps, rubella, and varicella viruses. ProQuad is a sterile lyophilized preparation of the components of M-M-R II (Measles, Mumps, and Rubella Virus Vaccine Live): Measles Virus Vaccine Live, and Varicella Virus Vaccine Live (Oka/Merck), the Oka/Merck strain of varicella-zoster virus propagated in MRC-5 cells. MRC-5 cells are derived from a cell line developed in 1966 from lung tissue of a 14-week aborted fetus and contains viral antigens. 

The growth medium for measles and mumps in both MMRII and ProQuad is a buffered salt solution containing vitamins and amino acids and it is supplemented with fetal bovine serum containing sucrose, phosphate, glutamate, recombinant human albumin, and neomycin. The growth medium for rubella is a buffered salt solution containing vitamins and amino acids and supplemented with fetal bovine serum containing recombinant human albumin and neomycin. Sorbitol and hydrolyzed gelatin stabilizer are added to the individual virus harvests. In the ProQuad vaccine, the Oka/Merck strain of the live attenuated varicella virus, initially obtained from a child with wild-type varicella, introduced into human embryonic lung cell cultures, adapted to and propagated in embryonic guinea pig cell cultures and human diploid cell cultures (WI-38), is then added to the MMRII component.

According to Merck, both MMRII and ProQuad vaccines are screened for adventitious agents. Each dose of MMRII contains sorbitol, sodium phosphate, sucrose, sodium chloride, hydrolyzed gelatin, recombinant human albumin, fetal bovine serum, other buffer and media ingredients and neomycin. Each dose of ProQuad contains sucrose, hydrolyzed gelatin, sorbitol, MSG, sodium phosphate, human albumin, sodium bicarbonate, potassium phosphate and chloride, neomycin, bovine calf serum, chick embryo cell culture, WI-38 human diploid lung fibroblasts and MRC-5 cells. 

The MMRII vaccine product information inserts states that the MMRII vaccine should be given one month before or one month after any other live viral vaccines. The ProQuad vaccine product information insert states that one month should lapse between administration of ProQuad and another measles containing vaccine such as MMRII and at least three months should lapse between ProQuad and any varicella containing vaccine. 

The CDC currently recommends that children receive two doses of a measles containing vaccine, with the first dose administered between 12-15 months, and the second dose between 4-6 years. The CDC also recommends that individuals born after 1957 and have no laboratory evidence of immunity or documentation of vaccination should receive at least one dose of MMR vaccine. Two doses of MMR vaccine are also recommended for healthcare personnel, students entering college and other post-high school educational institutions, and international travelers. 

MMR vaccination is recommended by the CDC for infants between 6 and 11 months of age who may be traveling internationally; however, ProQuad and MMRII are only FDA approved for use in children 12 months and older. The MMRII vaccine product insert states that the effectiveness and safety of MMRII has not been established in children between 6 and 11 months and if administered to this population, antibodies may not develop. According to the CDC, an infant vaccinated prior to 12 months of age will still require two additional doses of MMR vaccine.

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Source: NVIC.ORG 

Guillain-Barré syndrome, an autoimmune polyneuropathy, has become the most common cause of acute generalized paralysis and is thought to be immune-mediated. It is preceded by upper respiratory or gastrointestinal infection in about two-thirds of cases and is associated with some viral infections, including influenza. GBS affects individuals of all ages but is rare in infancy. GBS has been attributed to certain vaccinations, particularly, in relation to monovalent or combination measles, mumps, and rubella vaccines, influenza vaccine, oral polio vaccine, diphtheria and tetanus toxoids. GBS has also been associated with the 1976 swine-influenza vaccine. Thereafter, some studies have shown an increased risk of GBS following receipt of seasonal and 2009 H1N1 monovalent influenza vaccines. Studies over the years have also shown an increased risk of GBS following influenza infection, and the magnitude of risk is several times greater than that following influenza vaccination.

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Autism is a complex disorder of the central nervous system (CNS), manifesting both neurological as well as behavioral impairments. The disorder causes severe deficits of higher mental functions such as social interaction, language, communication, imagination, and cognition. The etiology and pathogenesis of the disorder is not well known or established. Current theories include genetic factors, immune factors, viral factors, neural factors, and yet other unidentified factors.

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Because viruses are common trigger agents for autoimmune diseases such as GBS, it has also been proposed that a virus-induced autoimmune response may play a causal role in autism. Vaccination of the measles virus, mumps virus, and rubella virus has been implicated as a cause or co-cause of autism. In particular, elevated levels of measles antibodies in autistic children are a possible consequence of a misguided immune response to measles vaccine.

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Articles MMR Vaccine Reactions

Dourado, Ines, Sergio Cunha, Maria da Gloria Teixeira, C. Paddy Farrington, Ailton Melo, Rita Lucena, and Maurício L. Barreto. "Outbreak of aseptic meningitis associated with mass vaccination with a urabe-containing measles-mumps-rubella vaccine: implications for immunization programs." American journal of epidemiology 151, no. 5 (2000): 524-530.

 

Abstract

A mass immunization campaign with a Urabe-containing measles-mumps-rubella vaccine was carried out in 1997 in the city of Salvador, northeastern Brazil, with a target population of children aged 1-11 years. There was an outbreak of aseptic meningitis following the mass campaign. Cases of aseptic meningitis were ascertained through data collected from the records of children admitted to the local referral hospital for infectious diseases between March and October of 1997, using previously defined eligibility criteria. Vaccination histories were obtained through home visits or telephone calls. Eighty-seven cases fulfilled the study criteria. Of those, 58 cases were diagnosed after the vaccination campaign. An elevated risk of aseptic meningitis was observed 3 weeks after Brazil's national vaccination day compared with the risk in the prevaccination period (relative risk = 14.3; 95% confidence interval: 7.9, 25.7). This result was confirmed by a case series analysis (relative risk = 30.4; 95% confidence interval: 11.5, 80.8). The estimated risk of aseptic meningitis was 1 in 14,000 doses. This study confirms a link between measles-mumps-rubella vaccination and aseptic meningitis. The authors discuss the implications of this for the organization and planning of mass immunization campaigns. 

Miller, Elizabeth, P. Farrington, M. Goldracre, S. Pugh, A. Colville, Audrey Flower, James Nash, Lorna MacFarlane, and Richard Tettmar. "Risk of aseptic meningitis after measles, mumps, and rubella vaccine in UK children." The Lancet 341, no. 8851 (1993): 979-982.

 

Abstract

Cases of aseptic meningitis associated with measles/mumps/rubella vaccine were sought in thirteen UK health districts following a reported cluster in Nottingham which suggested a risk of 1 in 4000 doses, substantially higher than previous estimates based on cases reported by paediatricians (4 per million). Cases were ascertained by obtaining vaccination records of children with aseptic meningitis diagnosed from cerebrospinal fluid samples submitted to Public Health Laboratories or discharged from hospital with a diagnosis of viral meningitis. Both methods identified vaccination 15-35 days before onset as a significant risk factor and therefore indicative of a causal association. With both, half the aseptic meningitis cases identified in children aged 12-24 months were vaccine-associated with onset 15-35 days after vaccine. The study confirmed that the true risk was substantially higher than suggested by case reports from pediatricians, probably about 1 in 11 000 doses. However, the possibility that the aseptic meningitis induced by vaccination was largely asymptomatic and a chance laboratory finding in children investigated for other clinical conditions, particularly febrile convulsions, could not be excluded. Comparison of national reports of virus-positive mumps meningitis cases before and after the introduction of this vaccine indicated that the risk from wild mumps was about 4-fold higher than from vaccine. Altogether, 28 vaccine-associated cases were identified, all in recipients of vaccines containing the Urabe mumps strain. The absence of cases in recipients of vaccine containing the Jeryl Lynn strain, despite its 14% market share, suggested a higher risk from Urabe vaccine. A prospective adverse event surveillance system using the study methods is currently being established to assess the risk, if any, from the Jeryl Lynn strain which is now the only mumps vaccine used in the UK.

 

Articles Measles Vaccine Reactions

Grose, Charles, and Ilya Spigland. "Guillain-Barré syndrome following administration of live measles vaccine." The American journal of medicine 60, no. 3 (1976): 441-443.

 

Abstract

In a 19-month-old girl and a 10-month-old girl the Guillain-Barré syndrome developed within a week after they received, respectively, live measles-rubella vaccine and live measles vaccine. The older child was immune to rubella at the time of vaccination, but both girls demonstrated a primary measles antibody response. Serum obtained during the acute and convalescent stages from the younger child was tested for antibodies against the herpes viruses (herpes simplex, Epstein-Barr virus, cytomegalovirus and varicella-zoster) and found to be negative.

Kawashima, Hisashi, Takayuki Mori, Yasuyo Kashiwagi, Kouji Takekuma, Akinori Hoshika, and Andrew Wakefield. "Detection and sequencing of measles virus from peripheral mononuclear cells from patients with inflammatory bowel disease and autism." Digestive diseases and sciences 45, no. 4 (2000): 723-729.

 

Abstract

It has been reported that measles virus may be present in the intestine of patients with Crohn’s disease. Additionally, a new syndrome has been reported in children with autism who exhibited developmental regression and gastrointestinal symptoms (autistic enterocolitis), in some cases soon after MMR vaccine. It is not known whether the virus, if confirmed to be present in these patients, derives from either wild strains or vaccine strains. In order to characterize the strains that may be present, we have carried out the detection of measles genomic RNA in peripheral mononuclear cells (PBMC) in eight patients with Crohn’s disease, three patients with ulcerative colitis, and nine children with autistic enterocolitis. As controls, we examined healthy children and patients with SSPE, SLE, HIV-1 (a total of eight cases). RNA was purified from PBMC by Ficoll-paque, followed by reverse transcription using AMV; cDNAs were subjected to nested PCR for detection of specific regions of the hemagglutinin (H) and fusion (F) gene regions. Positive samples were sequenced directly, in nucleotides 8393–8676 (H region) or 5325–5465 (from noncoding F to coding F region). One of eight patients with Crohn disease, one of three patients with ulcerative colitis, and three of nine children with autism, were positive. Controls were all negative. The sequences obtained from the patients with Crohn’s disease shared the characteristics with wild-strain virus. The sequences obtained from the patients with ulcerative colitis and children with autism were consistent with being vaccine strains. The results were concordant with the exposure history of the patients. Persistence of measles virus was confirmed in PBMC in some patients with chronic intestinal inflammation.

Landrigen PJ, Witte JJ. 1973. "Neurologic disorders following live measles virus vaccination." Journal of the American Medical Association 223:1459-1462.

 

Abstract

From 1963 through 1971, eighty-four cases of neurologic disorders with onset less than 30 days after live measles-virus vaccination were reported in the United States. Thirteen could be adequately accounted for by causes other than vaccine, and another 11 were uncomplicated febrile convulsions probably related to vaccination. One case met diagnostic criteria for subacute sclerosing panencephalitis. The remaining 59 showed clinical features of encephalitis or encephalopathy. Causes of these cases could not be established, but 45 (76%) had onset between 6 and 15 days after vaccination; this clustering suggests that some may have been caused by vaccine. From 1963 through 1971, 50.9 million doses of measles vaccine were distributed, and, therefore, incidence of the reported neurologic disorders was 1.16 per million doses. Risk of encephalitis following measles infection is one per thousand cases.

Quast, Ute, W. Hennessen, and R. M. Widmark. "Vaccine induced mumps-like diseases." Developments in Biological Standardization 43 (1979): 269.

 

Abstract

Sixteen cases of parotitis and 2 cases of diabetes mellitus after mumps vaccination have been reported since the introduction of the live attenuated mumps vaccine in the F. R. Germany in the fall of 1976. Due to the post-vaccination incubation of 7 to 10 days, support is given to the assumption that these cases are vaccine induced and not coincidental wild virus infections.

 

Articles Mumps Vaccine Reactions

Brown, E. G., J. Furesz, K. Dimock, W. Yarosh, and G. Contreras. "Nucleotide sequence analysis of Urabe mumps vaccine strain that caused meningitis in vaccine recipients." Vaccine 9, no. 11 (1991): 840-842.

 

Abstract

Mumps virus was isolated from the cerebrospinal fluid of eight patients who acquired meningitis within 4 weeks of immunization with live Trivirix vaccine that contains mumps (Urabe Am 9), measles (Schwarz), and rubella (RA 27/3) viruses. Part of the haemagglutinin-neuraminidase (HN) gene from three postvaccination isolates of mumps virus, three wild strains and the Urabe and Jeryl Lynn vaccine strains was cloned following polymerase chain reaction (PCR) amplification, for the purpose of sequence analysis. A 200-nucleotide portion of the cloned HN genes was sequenced and compared to published sequences of two other strains (RW and SBL-1). The postvaccination mumps strains were identical in sequence to Urabe and were distinguishable from the wild and the Jeryl Lynn vaccine strains. Twenty-two out of 200 position were seen to vary among the group of viruses. It was concluded that the Urabe vaccine strain was the cause of postvaccination meningitis. Therefore, with effect from 1990, Trivirix measles, mumps and rubella vaccine is no longer licensed for sale in Canada.

Cizman, M., M. Mozetic, R. Radescek-Rakar, D. Pleterski-Rigler, and M. Susec-Michieli. "Aseptic meningitis after vaccination against measles and mumps." The Pediatric infectious disease journal 8, no. 5 (1989): 302-308.

 

Abstract 

This retrospective study (1979 to 1986) investigated the possible etiologic relationship between vaccination and aseptic meningitis in 115 hospitalized children who became ill within 30 days of vaccination with the Leningrad 3 strain of mumps virus and the Edmonston-Zagreb strain of measles virus. The etiologic viral diagnosis was based on serologic tests and the isolation of virus from cell cultures which distinguished between attenuated and "virulent" mumps virus. The incidence of mumps vaccine-associated meningitis was 1/1000 vaccine recipients. In 92% of children the incubation period was 11 to 25 days and 28% had associated swelling of the salivary glands. Sixteen cases (13.9%) had a positive cerebrospinal fluid culture (attenuated mumps virus, 6 cases; "virulent" mumps virus, 7 cases; echoviruses, 3 cases). Clustering of cases, seasonal occurrence and age of the patients suggested causal relationship with the vaccination in the majority of children. In 4 patients with attenuated virus isolation from cerebrospinal fluid the incubation period ranged from 17 to 20 days. Clinical findings did not differ from natural mumps meningitis. The course was uncomplicated and at discharge the patients had no sequelae. Measles virus was never found as a cause of the meningitis. The mumps vaccine virus should be recognized as one of the causative agents of aseptic meningitis in countries where less attenuated mumps vaccine is used.

 

Sugiura, A., and A. Yamada. "Aseptic meningitis as a complication of mumps vaccination." The Pediatric infectious disease journal 10, no. 3 (1991): 209-213.

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Abstract

In 1989 a nationwide surveillance of neurologic complications after the administration of mumps vaccine was conducted in Japan, based on the notification of cases and the testing of mumps viruses isolated from cerebrospinal fluid for their relatedness to the vaccine by nucleotide sequence analysis. Among 630,157 recipients of measles-mumps-rubella trivalent (MMR) vaccine containing the Urabe Am9 mumps vaccine, there were at least 311 meningitis cases suspected to be vaccine-related. In 96 of these 311 cases, mumps virus related to the vaccine was isolated from cerebrospinal fluid. The unusually high incidence may have been partly a result of the adverse media publicity of the problem at the time of surveillance. We analyzed clinical features of 165 and 27 laboratory-confirmed mumps vaccine-related meningitis cases that occurred among the recipients of MMR and monovalent mumps vaccines, respectively, during a 1-year period after the introduction of MMR vaccine. The incidence of vaccine-related meningitis was similar among the recipients of MMR and monovalent Urabe Am9 mumps vaccines. Meningitis was generally mild and there were no sequelae from the illness. The complication was more frequent among male than among female children.

 

da Silveira, Claudio Marcos, Claudete Iris Kmetzsch, Renate Mohrdieck, Alethea Fagundes Sperb, and D. Rebecca Prevots. "The risk of aseptic meningitis associated with the Leningrad-Zagreb mumps vaccine strain following mass vaccination with measles-mumps-rubella vaccine, Rio Grande do Sul, Brazil, 1997." International journal of epidemiology 31, no. 5 (2002): 978-982.

 

Abstract

Background Few data are available on the risk of aseptic meningitis following vaccination with the Leningrad-Zagreb (L-Z) strain of mumps vaccine. In 1997 the mumps vaccine was introduced into the state of Rio Grande do Sul in Brazil through mass vaccination with mumps-measles-rubella (MMR), targeting children aged 1–11 years. Five municipalities used exclusively MMR vaccine containing the L-Z strain of mumps. An outbreak of aseptic meningitis was observed shortly after the mass campaign.

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Methods To estimate the risk of aseptic meningitis associated with this strain, we analysed vaccination and meningitis case surveillance data from the selected municipalities. A case of vaccine-associated aseptic meningitis was defined as one with a pleocytosis of 10–1500 leukocytes/ml and occurring within 15–35 days after vaccine receipt.

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Results We estimated a risk of 2.9 cases per 10 000 doses of L-Z administered, equivalent to 1 case per 3390 doses administered. The overall risk of aseptic meningitis following the campaign was increased 12.2-fold (95% CI: 6.0–24.7) compared with the same period in 1995–1996. Following the mass campaign, the incidence of mumps declined 93% during 1998–2000.

Conclusions Vaccination with the L-Z strain of mumps vaccine as part of a mass campaign was associated with a significantly increased risk of aseptic meningitis. Decisions about type of mumps vaccine and mumps vaccination strategies must consider vaccine safety issues in addition to other criteria.

 

Articles Rubella Vaccine Reactions

 

Mitchell, Leslie A., Aubrey J. Tingle, Robert Shukin, Jon A. Sangeorzan, Joseph McCune, and Daniel K. Braun. "Chronic rubella vaccine-associated arthropathy." Archives of internal medicine 153, no. 19 (1993): 2268-2274.

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Abstract

Rubella immunization or infection is an uncommonly recognized cause of acute, recurrent, or persistent musculoskeletal manifestations. After routine rubella immunization, two women presented with the onset of polyarthralgia, arthritis, maculopapular rash, fever, paresthesia, and malaise with persistent or recurrent manifestations lasting longer than 24 months after vaccination. The patients expressed rubella virus RNA in peripheral-blood leukocytes 10 and 8 months after vaccination, respectively, in contrast to repeated negative results in asymptomatic rubella-immunized controls. One patient developed significantly depressed antibody responses to rubella virus after vaccination and experienced a prolonged clinical improvement after a 3-month course of intravenous immune globulin. The second patient had normal antibody responses to rubella virus and underwent no clinical improvement during or after intravenous immune globulin therapy. Rubella immunization or infection should be considered as additional causative factors in evaluation of acute and continuing musculoskeletal syndromes.

 

Tingle, Aubrey J., Janet K. Chantler, Kees H. Pot, Donald W. Paty, and Denys K. Ford. "Postpartum rubella immunization: association with development of prolonged arthritis, neurological sequelae, and chronic rubella viremia." Journal of Infectious Diseases 152, no. 3 (1985): 606-612.

 

Abstract

Six women developed chronic long-term arthropathy after postpartum immunization against rubella. All individuals developed acute polyarticular arthritis within 12days to three weeks postimmunization and have had continuing chronic or recurrent arthralgia or arthritis for two to seven years after vaccination. Acute neurological manifestations, consisting of carpal tunnel syndrome or multiple paresthesia, developed postvaccination in three women. Two have developed continuing active or chronic recurrent episodes of blurred vision, paresthesia, and painful limb syndromes together with recurrent joint symptoms. Chronic rubella viremia has been detected in peripheral blood mononuclear cell (MNC) populations in five of the six women up to six years after vaccination. In addition, rubella virus was isolated from breast milk MNCs in one individual at nine months postvaccination and from peripheral blood MNCs in two of four breast-fed infants studied at 12-18months of age. Immune responses to rubella virus studied at sequential intervals after vaccination correlated with development of rheumatologic and neurological manifestations.