life11e_ch41

Vaccines are an application of immunological memory

Thanks to immunological memory, exposure to many diseases (including childhood diseases such as chicken pox) provides a natural immunity to those diseases. Furthermore, it is possible to provide artificial immunity against many life-threatening diseases by vaccination: the introduction of antigen into the body in a form that does not cause disease.

Vaccination initiates a primary immune response, generating memory cells without making the person ill. Later, if a pathogen carrying the same antigen attacks, specific memory cells already exist. They recognize the antigen and quickly overwhelm the invaders with a massive production of lymphocytes and antibodies.

Because of mutation, an antigenic determinant on a pathogen can change over time. If the change is significant in terms of three-dimensional structure, a vaccine directed against an antigen from a pathogen may become ineffective. You are familiar with this with regard to influenza. More often than not, the annual flu season features a genetic strain of the flu virus that is not sufficiently related to the previous season’s vaccine; so a new vaccine, with new B cell clones, must be made. A remarkable recent finding is that memory cells can last a long time and help in a response to new, related antigens. People who were exposed to a particular strain of flu retain antibody-making memory cells against that strain for decades and develop a rapid immune response to a new, genetically different strain that appears years later. In the case of flu, the memory cells are making antibodies that bind to not just the first strain of flu they responded to, but to later ones as well. Characterizing these antibodies provides a clue to developing a vaccine that is broadly effective and obviates the need to develop new ones (Investigating Life: What Are the Mechanisms and Implications of Long-Lasting Immunity?).

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investigating life

What Are the Mechanisms and Implications of Long-Lasting Immunity?

experiment

Original Paper: Miller, M. et al. 2013. Neutralizing antibodies against previously encountered influenza virus strains increase over time: A longitudinal analysis. Science Translational Medicine 5: 1–9 (August 14 issue).

The Framingham Heart Study was begun in 1948 with the objective of finding out the causes of heart disease and stroke. About 5,000 people ages 30–62 and living in the town Framingham, Massachusetts, have been subjected every 2 years to extensive medical exams in an attempt to relate lifestyle factors to heart disease. Subsequent generations have been added to the study ever since. Not only has this study led to major findings about the causes of heart disease, but it has provided a wealth of data on other medical conditions as well. Peter Palese of the Icahn School of Medicine at Mount Sinai Hospital in New York City measured antibodies in blood to flu virus strains from 40 people in the Framingham study, born between 1917 and 1952. They had been exposed to major flu outbreaks in 1957, 1968, and 1977, as well as to the typical flu that comes up every year. Blood samples were examined between 1987 and 2008 to see if these people still had antibodies against the three major flu outbreak strains, and whether these antibody amounts increased over time as people fought off the new, less virulent strains that arise every year.

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work with the data

QUESTIONS

Question 1

Blood samples were taken from 1987 to 2008, and the people’s reactivity against various flu strains was tested. The results for antibodies against the Russian flu strain of 1977 in numerous individuals are shown in Figure A. Note that these people were exposed to many flu strains after 1977. The data shown are typical for the way specific immune reactions are measured. The titer is presented as a reciprocal. For example, a titer of 2 means that undiluted serum sample gave an antibody reaction (titer 1), and so did a dilution of 1 part serum and 1 part water (dilution of 1/2, reciprocal = 2). If the sample was diluted to a titer of 4 (1 part serum, 3 parts water), there was no reaction because the concentration of antibody was too low. The higher the titer number, the more the blood serum could be diluted to still react with the antigen; that is, a higher titer number means that there were more antibodies in the original serum sample. What can you conclude about the titer of anti-Russian flu strain over the years 1987–2008?

While some people had low titers and other had high titers of anti-Russian flu antibodies, the general trend over time was for the titers to increase. As these people were exposed to the typical flu strains year after year, their anti-flu virus responses, including to the Russian flu, increased. This indicates that there were some general antibodies that bind to all flu strains.

Question 2

The flu virus mutates rapidly. In contrast, another virus to which people are exposed, cytomegalovirus (CMV), does not mutate rapidly. Antibody titer against CMV were measured, and the data are shown in Figure B. What can you conclude from these data? Compare the antibody response to CMV over time with that against the Russian flu virus strain and comment.

There was little change in the antibody titers to CMV. Note that the y axis is much lower quantitatively in this case than the y axis for anti-flu titers. CMV has epitopes unrelated to the flu virus, so anti-CMV antibodies will not be made when a person is exposed to flu. The data indicate that the increase in flu virus strain immunity was flu virus–specific.

Question 3

A protein on the surface of the flu virus called hemagluttinin (HA) is exposed to the immune system because of its prominent location (Figure C). When the flu virus genes mutate, the “head” of the protein tends to accumulate more changes than the stalk. Thus the amino acid sequences of stalk regions of various flu strains are similar. The investigators measured antibodies to the stalk region that were either broadly reactive to various flu strains, or not broadly reactive. The results are shown in the table. What can you conclude about the broadly reactive antibodies? How does this provide a guide for the development of a broadly based flu vaccine?

The antibodies that developed were mostly broadly reactive. These antibodies could be used to develop a vaccine that might work on old as well as new strains of flu virus.

A similar work with the data exercise may be assigned in LaunchPad.

As you saw in the opening story, vaccination has completely or almost completely wiped out some deadly diseases in industrialized countries.