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

Hanne Nøkleby

Disclosures

Expert Rev Vaccines. 2007;6(5):863-869. 

In This Article

Expert Commentary & Five-Year View

For 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]

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