Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 9th Canadian Immunization Conference (CIC)

Quebec City, Quebec / December 5-8, 2010

After clean water, vaccines have been the most effective medical intervention in history. Vaccines work by inducing immunity. The mechanism of action is complex, but there are two main pathways through which vaccines induce immune-mediated protection: antibodies and T-cell-mediated effector mechanisms. “Antibodies can prevent, for example, a virus from finding its key, that is, a receptor on the cell surface, and prevent it from locking in,” explained Dr. Tobias Kollmann, Vaccine Evaluation Centre, University of British Columbia (UBC), Vancouver, “while T-cells produce a cocktail of cytokines that rev up surrounding cells to either gobble up invaders or inject toxic granules into infected cells, killing them.”

Adjuvants are a pivotal component of vaccines, he continued, because they activate key immune cells; in the absence of this activation, immune cells cannot protect against infection. At first, researchers designed whole-cell vaccines such as the pertussis vaccine which contained thousands of proteins. Over time, the number of components contained in subunit vaccines dropped to single digits, attenuating reactogenicity and systemic side effects but also decreasing immunogenicity in the process—“so you need to add back adjuvants to increase activity,” Dr. Kollmann noted.

The innate immune system needs to be activated first, dendritic cells in particular, which control the induction, the quality and the quantity of the vaccine-specific adaptive immunity. “Adjuvants make activation much more likely to occur,” Dr. Kollmann said, through both the induction and expression of co-stimulatory molecules and cytokines. Adjuvants accomplish this through innate sentinel sensors that recognize danger in the form of infectious microbes from the outside or cell injury from the inside.

“This is what adjuvants target,” Dr. Kollmann confirmed. “Adjuvants activate innate receptors that recognize danger signals; these receptors simulate inside or outside danger signals and affect the final protective effect of adaptive immune responses quantitatively—by inducing protection earlier, longer or higher—and qualitatively by determining what specific type of adaptive immune response is induced.”

Early and Late in Life

The use of adjuvants in vaccines is particularly important late in life when the immune system needs greater prompting to induce protective responses. “Specifically, the T-cell response deteriorates with age and that is why you need to trigger cytotoxic T-cell responses that kill the virus,” Dr. Janet McElhaney, Professor and Allan McGavin Chair in Geriatrics Research, UBC, noted in an interview. Prevention of influenza in the elderly is a good model of what can be done to preserve the health of older individuals. “Influenza is the single most vaccine-preventable disease in the elderly and vaccination programs are cost-saving in older people,” she emphasized.

At the same time, influenza remains a serious illness in the elderly: 90% of deaths from influenza occur in older patients and for every influenza death, there are 3 to 4 hospitalizations. Subsequent disability from an episode of influenza is also serious. Even among patients who are aging normally, 80% have 1 underlying chronic condition and 50% have 2 or more, “so this is not a population that can have the same response to vaccination as younger patients,” Dr. McElhaney remarked. Add in an episode of influenza, “and it can move these individuals into a frail senior category who require long-term care,” she added. Indeed, if an older patient needs to be hospitalized because of influenza, they can lose up to 5% of their functional muscle strength each day, and most patients who experience an influenza-related hospitalization never recover following discharge back to the community.

The leading causes of catastrophic disability, i.e. that a patient will lose 3 or more important activities of daily living due to a single acute illness, have all been linked to influenza as well. “Vaccine-preventable disability” thus becomes a key goal in the management of older patients and the risk of serious disability can be minimized through vaccination.

The issue with split-virus influenza vaccines is that they are only 30 to 40% effective at preventing influenza illness (although they are quite effective at preventing hospitalization, as Dr. McElhaney emphasized). “When we vaccinate older patients with the current split-virus vaccines, they present viral antigens to T-helper cells so you get good antibody responses but they are not very good at stimulating cytotoxic T-lymphocyte responses,” she explained.

More Effective Vaccines

More effective influenza vaccines therefore need to target antigen presenting cells (dendritic cells) to stimulate better cytotoxic T-cell responses. In her own research, Dr. McElhaney has shown that the level of granzyme B, which is produced in cytotoxic T-lymphocytes and which is a key mediator of cytotoxic activity against virus-infected cells, can predict response to influenza vaccine. For example, elderly subjects who exhibit high levels of granzyme B in ex vivo cultures of peripheral blood mononuclear cells stimulated with influenza virus are more likely to be protected against infection than those who produce lower levels. This suggests that older patients who are less likely to respond to current influenza vaccines may be identified and targeted with new vaccines that invoke stronger cytotoxic T-cell responses and enhanced viral killing.

Dr. McElhaney also noted that because “natural” influenza infection is the “perfect” vaccine, “we can tell patients that if they had not been vaccinated and still got influenza, they would have been a lot sicker than they were and the next year when they get the influenza vaccine, they are going to mount a really good response.”

Vaccine Trial Findings

To demonstrate vaccine efficacy, vaccine trials would need to enrol many thousands of patients; consequently, comparisons between vaccines use surrogate measures of vaccine efficacy, notably antibody responses to the vaccine.

With investigative work showing the MF59 adjuvant to be the most potent adjuvant available for influenza vaccines, Ansaldi et al. (Vaccine 2008;26:1525-9) compared the ability of MF59 adjuvants and non-adjuvanted subunit influenza vaccines to confer cross-protection against 4 drifted strains in the elderly. Both vaccines contained A/Wyoming/3/03(H3N2). Neutralizing (NT) and hemagglutination-inhibiting (HI) antibody were each measured. As the authors noted, A/Panama/2007/99(H3N2) had circulated widely during the previous 5 years and was included in vaccines over 4 consecutive seasons.

“Subjects vaccinated with the MF59-adjuvanted vaccine showed significantly higher post-vaccination HI and NT geometric mean titres (GMTs) and a significantly higher seroconversion rate against the vaccine strain (Wyo/03) than those in the non-adjuvanted vaccine group,” the authors reported, even though seroprotection rates for both vaccines were high at =96%. For the drifted strains, “only the MF59-adjuvanted vaccine induced a substantial immune response,” the authors added. They also noted that the appearance of drifted strains with an antigenic pattern that is substantially different from the vaccine strain highlights a limitation of non-adjuvanted vaccines to elicit an effective immune response.

More robust immune responses also appear to translate into important clinical benefits. Puig-Barbera et al. (Vaccine 2007;25:7317-21) carried out 3 case-control studies during the 2004-2005 influenza seasons in 3 health districts in Valencia, Spain. A total of 105,454 elderly subjects >64 years of age received the MF59-adjuvanted influenza vaccine. Over the influenza seasons, a total of 159 patients were hospitalized for acute coronary syndromes (ACS), 148 for cerebrovascular accidents (CVA) and 242 for pneumonia.

“The risk of hospitalization after the start of the influenza seasons was significantly lower in vaccinated patients compared with non-vaccinated patients,” the authors reported: hospitalization risk for ACS was reduced by 11% (OR 0.89), for CVA by 34% (OR 0.66) and for pneumonia by 27% (OR 0.73). Patients who were admitted for surgery or trauma served as controls in this study.

Importantly, the addition of the adjuvant has not been shown to affect its safety profile and the vaccine has been well tolerated in all clinical trials carried out in the elderly as well as younger recipients.

The influenza vaccines containing MF59 have been used widely in many European countries since 2000, and will likely be available in Canada in the near future.

Note: At the time of printing, the MF59-adjuvanted seasonal influenza vaccine is not licensed in Canada.