How to build a better flu vaccine

According to recent estimates from the CDC, in six influenza seasons, starting in 2005-06, flu vaccination against a variety of strains prevented 13.59 million cases.
(Paul Abell / AP Images for Sanofi Pasteur)

The Spanish flu pandemic of 1918-19 killed 583,135 Americans, according to public health authorities at the time.

Although we no longer suffer such a high rate of flu deaths, during a non-pandemic season, flu still kills on average thousands each year in this country. From the 1976-77 season to the 2006-07 season, flu-associated deaths ranged from a low of about 3,000 to a high of about 49,000, according to the national Centers for Disease Control and Prevention.

Vaccination is the key to prevention. According to recent estimates from the CDC, in six influenza seasons, starting in 2005-06, flu vaccination against a variety of strains prevented 13.59 million cases (and as a result, 5.8 million medically attended illnesses and 112,875 hospital admissions).


Because flu viruses mutate frequently, vaccines are reformulated each winter as a mixture of virus strains predicted to prevail during the next season. Depending on how good those selections are, during a given season the overall effectiveness is usually in the range of 50% to 80%.

But within the population, vaccines’ effectiveness varies widely because it is affected by various factors, including the general health and age of the recipient. Although people 65 and older make up only 15% of the U.S. population, on average they account for about 60% of the 200,000 hospitalizations and 90% of the thousands of deaths attributed to seasonal flu and its complications each year.

This phenomenon is due at least in part to poor responses to flu vaccines in the elderly. Scientists at the National Institutes of Health reviewed 31 vaccine antibody response studies conducted from 1986 to 2002 comparing groups of elderly and younger adults. They concluded that “the antibody response in the elderly is considerably lower than in younger adults” and called for “more immunogenic vaccine formulations for the elderly.”

These data are consistent with the analysis by the CDC of the 2012-13 flu season, which found that the vaccines’ effectiveness for all ages against influenza A subtype H3N2, the most common strain during that season, was 44%, compared with only 19% for people older than 64.

A bit of promising news is the preliminary conclusion of a large-scale, multi-center efficacy trial in people 65 or older of a vaccine formulation that contained four times the amount of antigen (the stuff against which the immune response is targeted). But it boosted the response rate from 19% to only 23.6%, which is far from satisfactory. We need clinical studies to find ways to do better. Much better.

Scientists at the Food and Drug Administration and the University of Miami Miller School of Medicine recently provided a physiological explanation for the age-related differences in effectiveness of flu vaccine: diminished levels of activity of a key immune system enzyme in people 50 to 80 years old. That decrease correlates with “a decline in the ability of the immune system to ‘redesign’ antibodies so they become increasingly more effective against influenza.”

These epidemiological and biochemical findings indicate a need to study systematically ways to increase the effectiveness of flu vaccination in the elderly. In their article reviewing antibody response studies, the NIH group offered several suggestions for future clinical trials of vaccine efficacy (against any strain of flu) in the elderly.

• Stratify over-65 subjects into five- to 10-year age groups.

• Gather data on whether subjects had been vaccinated during the previous flu season.

• Ascertain whether individual subjects live in an institution (such as a nursing home) or independently.

• Measure all of the three standard blood tests that quantify the response to vaccines.

I would add several more:

• Include vaccines of two types — one with virus that is inactivated and another with live but weakened virus — in separate groups in the study. Include vaccines with and without adjuvants (chemicals mixed with the viral antigen to boost the immune response).

• Study the effects of increased amounts of vaccine and more doses.

If there are any such formulations sufficiently advanced, we could also add to the list of variables a “universal” flu vaccine, the holy grail of flu prevention: a vaccine that would target a part of the virus that remains unchanged among different strains in spite of new mutations, so that a vaccination could protect against even novel strains for many flu seasons. The drug company Sanofi has taken such a vaccine to the stage of testing in animals.

In order to study all of these variables and to get the necessary statistical power for meaningful results, such a complex trial would require thousands of patients and tens of millions of dollars. But the knowledge gained could ultimately reduce morbidity and mortality in the elderly and provide a significant public health advance, especially in the event of a pandemic.

Henry I. Miller, a physician and molecular biologist, is a fellow at Stanford University’s Hoover Institution. He was the founding director of the FDA’s Office of Biotechnology from 1989 to 1993.