Neurological Adverse Events of Immunization: Experience With an Aluminum Adjuvanted Meningococcal B Outer Membrane Vesicle Vaccine

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http://www.medscape.com/viewarticle/565691Neurological

Adverse Events of Immunization: Experience With an Aluminum Adjuvanted

Meningococcal B Outer Membrane Vesicle VaccineHanne NøklebyExpert Rev Vaccines. 2007;6(5):863-869. ©2007 Future Drugs Ltd.Posted 11/20/2007Abstract and IntroductionAbstractThroughout

the history of vaccination, vaccines have been accused of harmful side

effects. Adverse events following immunization may be caused by the

active antigen in the vaccine or other constituents, such as adjuvants,

or may merely be coincidental. Possible neurological side effects have

always obtained high attention. However, the risk of serious events

caused by existing vaccines or aluminum adjuvants is very small.

Currently, there are several new vaccines and adjuvants in the

pipeline. Of these vaccines, many will be offered mainly to adolescents

or adults. When taken into general use, some of them will probably be

associated with serious adverse events. Although coincidence will be

the most probable explanation in most cases, causality will have to be

discussed in many situations. Preparing to address the causes of these

adverse events is important.IntroductionThe history of

vaccines and vaccination is one long battle, rolling back and forth

between victories over diseases and distrust caused by the alleged

harmful effects of the vaccines.[1] Some of the harmful

effects have been real, caused by deficient production or control of

the vaccines. In 1929 and 1930, the use of the bacille Calmette-Guérin

(BCG) vaccine made from a contaminated BCG strain led to the deaths of

at least 72 infants in Lübeck, Germany.[2] Another tragic

consequence of deficient control was the ‘Cutter incident’, where an

incompletely inactivated polio vaccine infected 120,000 children, and

led to disease in 40,000 of these cases. At least 51 vaccinates were

permanently paralyzed and five died.[3] Conversely, as

powerful prophylactic measures, the vaccines have also been victims of

the ‘paradox of prophylaxis’. Successful prophylaxis removes the

disease, thereby making minor or alleged negative vaccine effects very

visible with obvious consequences. Recent examples are the events

regarding the MMR vaccine and autism,[4] and thimerosal causing different neurological events.[5] Both allegations have been rejected by large and thorough studies.[6]Guillain-Barré Syndrome & Other Serious Neurological Adverse Events Following Vaccination

Until now, medical science cannot completely explain the cause of or

mechanisms behind the development of serious neurological diseases,

such as multiple sclerosis (MS), autism, Guillain-Barré syndrome (GBS)

or general encephalopathy. Some of the diseases have definite genetic

risk factors, while others are probably linked to infections. However,

this is not enough to explain the whole picture, especially why some

people develop serious diseases, while others in similar situations are

not affected. As all these diseases do appear from time to time without

obvious reasons, some individuals will necessarily develop such

‘inexplicable’ diseases during the period after vaccination, when

vaccines are administered to large groups of healthy people. This leads

to the question of whether these are causal relationships or just

coinciding events( Table 1 ). Pertussis Vaccine & EncephalopathyThe

first reports of seizures, encephalopathy and other signs of

neurological pathology after vaccination came shortly after whole-cell

pertussis vaccine was taken into general use more than 50 years ago.[7]

As pertussis became rare as a result of vaccination, the focus on

adverse events increased and the vaccine coverage dropped in several

countries, resulting in large pertussis outbreaks and some deaths.[8]

This was the starting point for the really large epidemiological study

trying to determine the relationship between pertussis vaccination and

encephalopathy, the British National Childhood Encephalopathy Study

(NCES). The NCES concluded that the pertussis vaccine might cause

serious neurological effects in approximately one in 100,000 cases.[9]

Further studies found no significantly increased risk of serious acute

neurological illness after the diphtheria, tetanus and pertussis (DTP)

vaccination, but the data were compatible with the concept that

vaccine-induced fever could possibly lead to an illness to which the

child was predisposed, such as febrile convulsions.[10] Despite many large studies, the lack of a causal relationship has never been totally accepted.[11] From a practical point of view, the problem was solved by the introduction of acellular pertussis vaccines.Oral Polio Vaccine: Associations With Poliomyelitis & GBSOral

polio vaccine (OPV) has been the most important tool in the worldwide

campaign attempting to eradicate poliomyelitis. The vaccine is

inexpensive, effective and easy to administer. However, as the vaccine

contains live-attenuated polio virus, there is a risk of

vaccine-associated poliomyelitis (one in 2.4 million doses).[12] Therefore, many countries without endemic polio have switched to an inactivated polio vaccine.[13]

A nationwide OPV vaccination campaign in Finland in 1985 raised the

question of a relationship between OPV and GBS, but in-depth analysis

of the data showed that the increase in GBS occurred before the

vaccination campaign started.[14]Influenza Vaccine & GBSConcerns

about the risk of developing GBS after vaccination have been present

since the mass vaccination with the A/New Jersey/H1N1 vaccine in the

USA in 1976-1977. Nearly the entire adult population was vaccinated,

using more than 35 million doses of the vaccine. A significantly

increased risk of GBS became evident within 6-8 weeks after

vaccination, with the largest percentage of cases occurring 2-3 weeks

after vaccination. The vaccine probably caused approximately one extra

case of GBS per 100,000 immunized persons.[15,16] The risk

was later shown to be associated with the vaccine made from the A/New

Jersey/H1N1 strain. The risk of GBS from other influenza vaccines has

been followed closely in several studies and has been shown to be much

lower, approximately one extra case per million people vaccinated.[17]

According to data from the Vaccine Adverse Event Reporting System

(VAERS) database, the incidence in the USA has fallen significantly

from the 1993-1994 vaccine season (0.17 per 100,000 vaccinees) to the

2002-2003 season (0.04 per 100,000 vaccinees).[18] A

possible explanation of the relationship between the influenza vaccine

and GBS is that the eggs used for vaccine production may have been

contaminated with Campylobacter. Campylobacter infection is a well-known cause of GBS. Better control of Campylobacter

infections in chicken and eggs, especially eggs used for vaccine

production, might explain the contemporary reduced incidence of

influenza vaccine-associated cases of GBS.[18] However, it is impossible to exclude that some influenza vaccines may represent a higher risk of GBS, independent of the Campylobacter

explanation. This is an important point when discussing

mass-vaccination campaigns in a possible new influenza pandemic

situation.MMR Vaccine & Neurological EventsAseptic

meningitis cases after MMR vaccination were reported from several

countries pre-1992. Detailed investigations showed that the cases were

related exclusively to MMR vaccines containing the Urabe mumps strain.

The risk of aseptic meningitis after vaccination with this mumps

vaccine was one in 10,000-15,000 people.[19] After the

withdrawal of vaccines with the Urabe mumps strain, the incidence of

aseptic meningitis has decreased to one in 437,000 doses or less,

according to a recent study from the UK.[19]Other

neurological events after MMR vaccination are rarely seen. GBS has been

reported both after vaccination with the MMR vaccine and the individual

vaccine components,[20] but a large Finish study found no

indication of a causal association between MMR vaccine and other

neurological events other than aseptic meningitis.[21]Hepatitis B Vaccine & MSThe

hepatitis B vaccine has been linked to different serious neurological

syndromes, such as GBS and transverse myelitis, but most of all to the

risk of MS. MS after hepatitis B vaccination has been reported most

commonly in France, possibly because France has implemented large

hepatitis B vaccination campaigns among adolescents and young adults.[22]

Some authors have reported an apparently plausible explanation based on

the fact that hepatitis B vaccine can lead to prolonged surface

antigenemia. The vaccine has, therefore, been associated with the same

kind of autoimmune symptoms or diseases that might be caused by

circulating immune complexes in chronic hepatitis B infection.[23] However, several large case-control studies recently reported no evidence of a link between hepatitis B vaccine and MS.[24,25]Aluminum-Adjuvanted VaccinesSerious

adverse events may be caused by different constituents in a vaccine:

the active antigen, an adjuvant such as potassium aluminium sulfate

(alum), a conservative agent such as thimerosal, or remnants from the

production process. If there is a suspicion that different vaccines

with some common constituents may cause the same kind of adverse

events, it is reasonable to look for possible effects of these

constituents rather than the active antigen.Aluminum salts

(aluminum hydroxide, aluminum phosphate and alum) have been the main

adjuvants used in vaccines for almost 80 years and are the only

adjuvants currently licensed for use in humans in the USA. Despite the

long experience, the mechanism of action still appears unclear. For

many years, the main effect of alum was believed to be keeping the

active antigen at the injection site and, therefore, available for

initial interaction with the immune system. However, experimental

studies have shown that the antigen disappears from the injection site

within a few hours.[26] The most important mechanism of alum

is probably mediated through activation of antigen-presenting cells.

Aluminum adjuvants also strongly influence the type of immune response

and are important for stimulation of antibody production but probably

do not induce cell-mediated immunity.[26]The most

widely used aluminum-adjuvanted vaccines have been tetanus and

diphtheria vaccines, with or without pertussis and other components

and, during the last 25 years, hepatitis B and A vaccines. The

worldwide impact of these vaccines on health has been enormous,[27] in spite of allegations of serious adverse effects.Adverse Effects Of Aluminum-Adjuvanted VaccinesLocal Adverse Effects.

There is a general agreement that vaccines with aluminum adjuvants

cause local reactions, such as pain at the injection site, erythema and

swelling lasting several days.[28] Sterile abscesses and

long-lasting itching nodules have also been described. Some authors

have attributed these nodules to a contact allergy to aluminum,[29] but this has not generally been accepted.[30]

Persistent nodules may be more common after subcutaneous than

intramuscular injection and are possibly more common in females than in

males.[31]General Adverse Effects. It has been claimed that aluminum adjuvants cause systemic adverse effects, although this is highly disputed.[28]

The most commonly used infant vaccine with aluminum adjuvant has been

the DTP vaccine. The administration of DTP vaccine to infants has been

associated with screaming, persistent crying, convulsions,

encephalopathy and hypotonic, hyporesponsive episodes, but these signs

have generally been linked to the pertussis component and not to the

adjuvant.Hepatitis A and B vaccines also usually contain

aluminum adjuvants. Although the hepatitis A vaccine has been

administered in millions of doses, there are very few reports of

serious adverse events linked to the vaccine.[23] This is

different for hepatitis B vaccines, but it would be difficult to

explain why the same adjuvant should cause serious neurological

diseases when used in one vaccine and no adverse events when used in

another. The possible adverse events of hepatitis B vaccine have

therefore been linked to the active antigen.[23]During

the last 15 years, a syndrome called macrophagic myofasciitis has been

associated with aluminum-adjuvanted vaccines. Most cases have been

reported in France and most of the patients have been adults,[32] but there are also descriptions of cases in other countries and in children.[33]

The patients have presented with a variety of clinical symptoms, but

usually they include myalgias, arthralgias, fatigue and, in some cases,

serious neurological diseases, such as MS. Muscular biopsies have, in

several cases, been taken from the deltoid region because of the

symptoms. The biopsies have shown macrophages surrounding the muscle

fibers forming a characteristic histological lesion. Electron

microscopy has shown the presence of aluminum hydroxide inclusions in

the lesions.[34] The patients have all been vaccinated with

different aluminum-containing vaccines from months to years before the

biopsy was taken.It now appears to be well established that

vaccines with aluminum adjuvants in some individuals are the cause of

the histologic lesion called ‘macrophagic myofasciitis’. It is

difficult to say how common such lesions may be for two reasons. The

size of the lesions may be very small and are, therefore, not always

caught by the biopsy. Also, it would be considered unethical to take

biopsies from healthy people, therefore, the true prevalence of these

lesions cannot be determined. However, the relationship between these

lesions and the clinical symptoms is still considered an unproven

hypothesis.[35,36]The Norwegian Experience With a Meningococcal B Outer-Membrane Vesicle Vaccine With Aluminum Hydroxide AdjuvantFrom

1975 to 1995, Norway experienced an epidemic of meningococcal group B

disease, with a maximal incidence rate of eight cases per 100,000.

Since no vaccine was commercially available at the time, the Norwegian

Institute of Public Health (NIPH) developed an outer-membrane vesicle

vaccine based on the prevalent epidemic strain, B:15:P1.7,16. The

vaccine was prepared by fermenter growth and extraction of the bacteria

with the detergent deoxycholate.[37] Each vaccine dose

contained 25 μg antigen and 1.65 mg aluminum hydroxide. The vaccine has

been evaluated in 28 clinical trials including three large Phase III

trials. One of these was a double-blind, school-randomized,

placebo-controlled trial that comprised 172,800 teenagers aged 13-16

years and was conducted from 1988 to 1991. In the trial, the vaccine

provided 57% protection over a period of 29 months, with an indication

of 87% protection during the first 10 months.[38] According

to the protocol, the placebo candidates were offered an active vaccine

after the code was broken in 1991. The second Phase III study consisted

of the follow-up of the total cohort after vaccination of the placebo

candidates with active vaccine.During these two trials, four

cases of serious inflammatory or demyelinating neurological diseases

were reported within 56 days of vaccination among the participants

receiving the active vaccine. Three of the cases occurred during the

first placebo-controlled Phase III trial. A previously healthy

12-year-old girl experienced myelopathy with weakness in both legs,

dysesthesia in her foot and calf and lack of sensation in bladder and

bowel 10 days after the first dose was administered. A previously

healthy 13-year-old boy with heredity for MS experienced a

demyelinating disease with transient hemiparesis 3 weeks after the

first dose. A previously healthy 13-year-old girl experienced

transverse myelitits with paresis and sensory disturbance in the lower

extremities 6 weeks after receiving the first dose. After vaccination

of the placebo candidates, an 18-year-old boy had the first symptoms of

GBS 21 days after the first vaccine dose was administered.In the

search for possible risk factors and plausibility of a causal

relationship to the vaccine, we focused on the following: the vaccine

did not contain meningococcal DNA. The possibility that antibodies to

meningococcal group B polysaccharide could cross-react to fetal brain

tissue was raised in 1983,[39] but the vaccine only

contained trace amounts of the group B polysaccharide. The vaccine did,

however, contain lipopolysaccharide (LPS) L3,7,9 (lacto-N-neotetraose)

and antibodies towards this epitope might possibly cause autoimmune

disease. However, there were no reports of increased risk of such

diseases after systemic meningococcal group B disease, when the amount

of LPS is much higher. There were also no reports of similar

neurological adverse events after trials with other meningococcal B

vaccines with similar LPS types.[40] Furthermore, there were

no such cases reported in the third Norwegian Phase III study, where

the vaccine had been administered to 27,500 military conscripts. The

vaccine also contained aluminum hydroxide as an adjuvant and there

were, at that time, suspicions of other aluminum-adjuvanted vaccines

causing similar reactions.[41] Therefore, we conducted an

epidemiological follow-up to evaluate the risk of serious inflammatory

or demyelinating neurological diseases after vaccination.The

epidemiological follow-up was performed on a cohort of 345,000 people

born between 1972 and 1977 and living in Norway during the trial years.

Of these, 144,000 had received at least one dose of vaccine, 91,000 in

1988-1989 and 53,000 additional individuals when the placebo candidates

were offered the vaccine in 1991. The total observation period was 3.5

years. During these years, a total of 57 cases of serious demyelinating

and inflammatory neurological diseases were registered. Only four

cases, all in vaccinees, appeared during the first 56 days after

vaccination. These cases had all been reported through the passive

reporting system of the trials, confirming that the system had been

able to catch all cases of serious neurological events. Based on these

figures and the observation time for the vaccinated and nonvaccinated

students, there was no statistically significant increased risk of CNS

demyelinating and inflammatory diseases in the first 8 weeks following

immunization (incidence rate ratio: 3.2; 95% confidence interval [CI]:

0.62-11; p = 0.16). For GBS syndrome the incidence rate ratio was 2.1

(95% CI: 0.048-14; p = 0.80). There was also no statistically

significant increased risk of serious CNS demyelinating and

inflammatory diseases or GBS in the 30-day period following vaccination

and no specific syndrome or disease pattern was discovered in teenagers

vaccinated with the meningococcal B vaccine.[42]Expert Commentary & Five-Year ViewFor

years, vaccines have been one of the most important tools in the fight

against infectious diseases but, so far, we have mostly developed the

‘easy vaccines’. For 25 years, we have been hoping that the advances in

molecular biology and recombinant technology might lead to new and more

advanced vaccines. The results applying these developments are now

beginning to appear. The first vaccine against human papilloma virus

(HPV) has become available recently. There are other vaccines in the

pipeline against herpes simplex, HIV, malaria and other important

diseases.One of the problems concerning the new generation of

vaccines has been achieving sufficient immune response or, just as

importantly, the mostappropriate response from the immune system. The

aluminum salts have not been sufficient to secure the desired effects.

Behind the present progress in vaccine development is also the

development of new and more effective adjuvants. Different lipid

adjuvants are already included in licensed vaccines in some countries,

such as virosomes,[43] the squalene-containing oil-in-water adjuvant MF59 (influenza vaccines)[44] or the MPL containing AS04 (hepatitis B vaccine).[45] More adjuvants are expected to follow, presumably resulting in new and more effective vaccines.Effective

vaccines are important but the safety of the vaccines is also very

important. New adjuvants may be effective by triggering other parts of

the immune system or eliciting new immunologic mechanisms compared with

existing vaccines. In-depth studies demonstrating the overall effect of

the adjuvants on the immune system will be necessary to avoid

surprising and negative consequences.[46]The target

groups for the new vaccines will, to a large extent, be adolescents or

adults. With mass vaccination in adolescents and adults, serious

diseases, such as GBS, chronic fatigue syndrome, MS and other

autoimmune and neurological diseases, will occur in the days or weeks

following vaccination, as they do in the same age groups without any

obvious cause. Some cases may appear already during large clinical

trials; more will be recognized if the vaccines are taken into general

use. Questions about purported causal relationships with the active

antigens or the adjuvants will have to be clarified.The

possibility of a new pandemic of influenza is also calling for new

vaccines. In a pandemic, we will presumably want to immunize as much of

the population as possible with the available vaccine, at least if the

pandemic virus turns out to be unusually virulent. However, based on

the 1976 experience in the USA, we already know that influenza vaccines

may be responsible for the development of GBS.[15] The

efforts to produce vaccines against the H5N1 strain have shown that

some influenza vaccines may need a large antigen content to give

sufficient response.[47] The alternative and only

possibility to secure sufficient quantities of vaccine will be to

develop adjuvanted vaccines. It has already been shown that aluminum

adjuvants may be helpful in this respect.[48] Newer

adjuvants may result in a sufficient effect with even smaller

quantities of antigen, thus making the vaccine available for more

people.Despite thorough knowledge about vaccine antigens and

adjuvants, and even if there have been large clinical trials for each

product, we must prepare to respond to the reports of serious adverse

events appearing when the vaccines are implemented in vaccination

programs or other types of general use. At least four elements will be

needed to meet this situation: a good registration system for adverse

events, methods to evaluate the possibility of causal relationships, an

acceptable compensation system and good communication skills to explain

the situation in a credible way to both health personnel and the public.Only

adverse effects occurring frequently, or at least not very rarely, will

be discovered during the clinical trials of new vaccines. However,

should there be the more serious events occurring in less than one in

10,000 vaccinees, they will only be revealed when the vaccine is taken

into general use. Notification, registration and follow-up of such

events will be necessary. This must be organized as postmarketing

surveillance[49] using a combination of active surveillance or postmarketing trials[19] and signal discovering databases, such as the VAERS.[50] International systems securing comparable information will be helpful to discover potential signals as soon as they arise.[51]

The signals must be followed up with the use of epidemiological

methods, such as case-control studies, database-linking studies or

time-trend analysis, to clarify possible causal relationships. Such

methods have shown their value in different situations, for example in

the debate on MMR vaccine and autism.[52]Vaccines are

developed because the medical community and society see the need for

protection against disease. In the developmental process, there is a

strong focus on safety in order to avoid any harmful side-effects.

However, if the vaccine, in spite of all preregulatory trials and

precautions, turns out to cause serious or even fatal disease,

compensation should be offered. There should, therefore, be a

well-functioning compensation system in place. As it sometimes will be

impossible to prove definitely that a single case is not associated

with the vaccine, no matter how good the investigative methods, the

threshold of certainty needed for awarding compensation in each single

case should be defined.A final challenge will be to address

potential public concerns in a way that gives credibility to the

efforts of securing good and safe vaccines. A good scientific basis for

all ingredients in the vaccines, sufficiently large clinical trials

before licensing and systems for postmarketing surveillance and

compensation that show the willingness to redress harm will provide the

best possible platform for communication.[53] Table 1. Neurological Adverse Events Following VaccinationVaccineAdverse eventCausality?Pertussis vaccineEncephalopathyPossiblyOral polio vaccineVaccine associated polioYes, 1/2.4 million dosesOral polio vaccineGuillain-Barré syndromeNoMMRAseptic meningitisYes, 1/10,000-15,000 doses for vaccines with the Urabe mumps strain. Very rare with presently used strainsMMRGuillain-Barré syndromeNoInfluenza vaccineGuillain-Barré syndromeYes. In 1976, A/New Jersey vaccine cases were 1/100,000 doses With other (later) vaccines less than 1/million dosesHepatitis B vaccineMultiple sclerosisProbably

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JJ, JD, Zangwill KM, Rowe T, Wolff M. Safety and

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Safety and immunogenicity of an inactivated adjuvanted whole-virion

influenza A (H5N1) vaccine: a Phase I randomised controlled trial. Lancet 368, 991-997 (2006).Ball R. Methods of ensuring vaccine safety. Expert Rev. Vaccines 1, 161-168 (2002).* Description of the necessity of and methods for establishing acceptance for the safety of vaccines.Iskander JK, ER, Chen RT. The role of the Vaccine Adverse Event Reporting System (VAERS) in monitoring vaccine safety. Pediatr. Ann. 33, 599-606 (2004).**

Describes the purposes, strengths and limitations of the Vaccine

Adverse Event Reporting System, underlining the importance of

discovering signals that may indicate the need for further

investigations of potential safety problems.Kohl KS, Bonhoeffer J, Chen R et al. The Brighton Collaboration: enhancing comparability of vaccine safety data. Pharmacoepidemiol. Drug Saf. 12, 335-340 (2003).Dales L, Hammer SJ, NJ. Time trends in autism and in MMR immunization coverage in California. JAMA 285, 1183-1185 (2001).Alaszewski A, Horlick- T. How can doctors communicate information about risk more effectively? Br. Med. J. (Clin. Res. Ed.) 377, 728-731 (2003).* Summary of factors that are necessary if doctors shall succeed in communication.Sidebar: Key IssuesAdverse events following

vaccination may be caused by the vaccine or may merely be coincidental.Serious neurological adverse events have, in almost all cases, been proven to be coincidental and not caused by the vaccine.Adverse

events may be caused by the active immunizing antigen or some other

constituent, such as an adjuvant. Aluminum adjuvants have been shown to

be very safe when used in vaccines.New vaccines

targeting mass vaccination of adolescents or adults will probably be

associated with serious adverse events and consequent discussions about

causality should take place.It is important to prepare for this situation in order to maintain the credibility of the vaccination efforts.Well-functioning

registration systems for adverse events, epidemiological tools to

evaluate the notifications of alleged vaccination-related adverse

effects and adequate compensation systems will be of major importance.DisclaimerNo writing assistance was utilized in the production of this manuscript.Reprint Address

Hanne Nøkleby, Norwegian Institute of Public Health, Division of

Infectious Disease Control, PO Box 4404 Nydalen, N-0403 Oslo, Norway.

E-mail: hanne.nokleby@...Hanne Nøkleby, Norwegian Institute of Public Health, Division of Infectious Disease ControlDisclosure:

The author has no relevant affiliations or financial involvement with

any organization or entity with a financial interest in or financial

conflict with the subject matter or materials discussed in the

manuscript. This includes employment, consultancies, honoraria, stock

ownership or options, expert testimony, grants or patents received or

pending, or royalties.