Association of excess mortality from chronic nonspecific lung disease with epidemics of influenza. Comparison of experience in the United States and in England and Wales, 1968 to 1976.

Mortality from chronic nonspecific lung disease reported in the United States and in England and Wales during the period 1968 to 1976 was studied to determine if excessive deaths from this condition were associated with epidemics of influenza. In both countries, peaks of excess mortality of this type did indeed occur during such epidemics; however, these excesses were considerably more marked in the British data where the estimated number of such deaths over the 8-yr period was 15,800 compared with 6,000 for the United States. There was a decreasing secular trend in age-specific death rates for chronic nonspecific lung disease among British males of all ages, whereas only middle-aged males showed such a trend in the United States; older American males were subject to a substantially increasing trend. The respective trends in such mortality observed among males in the 2 countries were also seen among females but were smaller in magnitude.

A study of excess mortality during influenza epidemics in the United States, 1968-1976.

The effect of epidemics of influenza A on mortality in the United States was assessed by studying the monthly numbers of deaths during the years 1968-1976. Deaths from all causes at all ages and among persons aged 65 and over, and also deaths from acute respiratory diseases, and from cardiovascular causes were studied. Deaths from acute respiratory diseases were closely correlated with those from influenza and were taken to be an indication of the severity of influenza outbreaks. This indicator combined with a regression function expressing seasonal variation and secular trend was used to predict total mortality, cardiovascular mortality, and deaths among persons aged 65 and over. In each case the predictions proved to be reasonably close to the observed numbers of deaths. Excess mortality from all causes above that expected from seasonal variation occurred principally in three periods during the eight years of study: 1968-1969, 1972-1973, and 1975-1976, each of which coincided with an epidemic of influenza A of the H3N2 subtype. Similar excesses were seen among persons aged 65 and over and in cardiovascular deaths during the two earlier periods. It is concluded that excess mortality occurred during at least three of the major outbreaks of influenza during the period 1968-1976. This points to the need of studying the effectiveness of immunization in preventing the disease.

Maxwell Finland lecture: the influenza viruses and the human respiratory tract.

This paper has reviewed evidence concerning the changes brought about in the structure and function of the lower airways by influenza virus infections. Disposal of inhaled bacteria is believed to be hindered by the mechanical damage to the epithelium of the respiratory tract caused by the virus infection, and phagocytosis is inhibited as well. Alteration in the ventilation, particularly of the peripheral small airways, which has been found in previously healthy persons during and after influenza, may add to the obstruction of the airways in those with chronic bronchitis and emphysema during influenza and may be important in the genesis of these disorders. The immunological defense of the respiratory tract against the influenza viruses has been discussed briefly with reference to the best available means of enhancing this defense, particularly in individuals with chronic pulmonary disease.

Dose-response relationship after immunization of volunteers with a new, surface-antigen-adsorbed influenza virus vaccine.

Volunteers (15 per group) were given inoculations of various doses (5-400 international units [IU]) of surface-antigen-adsorbed influenza virus A/Port Chalmers/73 vaccine; this vaccine was prepared from purified virus hemagglutinin and neuraminidase antigens and adsorbed to alhydrogel. The titers of hemagglutination-inhibiting (HAI) and neuraminidase-inhibiting antibodies in serum after immunization showed a clear dose-response relationship. Thus, for volunteers given 400, 100, 25, or 5.0 IU of vaccine, the titers of HAI antibody in serum increased 174-, 32-, 12-, and eightfold, respectively. A similar dose response was observed for production of local neutralizing antibody. Immunization with A/Port Chalmers/73 virus vaccine also induced serum HAI antibody to influenza viruses A/Scotland/74, A/England/72, and A/Hong Kong/68; the increase in titers of antibody to these viruses corresponded directly to the degree of cross-reactivity between the virus tested and the vaccine virus. Four weeks after immunization, all volunteers were challenged with attenuated WRL-105 influenza virus. Evidence of viral infection was found in one, two, and two volunteers in each group of 15 subjects previously immunized with 400, 100, and 25 IU of vaccine, respectively; in six of the 15 volunteers given 5.0 IU of vaccine; and in 10 of 15 control subjects. The results suggest that equivalent immunity was induced in volunteers given greater than or equal to 25 IU of vaccine.

A new surface-antigen-adsorbed influenza virus vaccine. II. Studies in a volunteer group.

A group of 23 volunteers were each inoculated with 600 CCA of a new form of influenza virus A/England/42/72 vaccine; this vaccine consisted of purified haemagglutinin and neuraminidase antigens adsorbed to alhydrogel. No significant reactions to the vaccine were reported. Twenty-two volunteers produced increased titres of serum HI antibody, and all showed increased titres of NI antibody after immunization. Thus, for volunteers with no pre-immunization serum HI antibody, the geometric mean titre of serum antibody increased from 1/5 to 1/196 after immunization. Ten volunteers developed local neutralizing antibody after immunization; this antibody response was detected most frequently in volunteers who showed the greater serum antibody response to immunization, and in nasal washings with the higher concentrations of protein and IgA. Ten weeks after immunization, the vaccinees and a group of matched controls were inoculated intranasally with attenuated A/England/42/72 virus. Evidence of infection with the challenge virus was found in 14 of the control subjects and in one of the vaccinees. The results indicate that the surface-antigen-adsorbed vaccine induced high titres of serum antibody, and gave significant protection against challenge infection.

Humoral and secretory antibody responses to immunization with low and high dosage split influenza virus vaccine.

Tri (n-butyl) phosphate (TNBP)-split vaccine containing 6400 CCA units of influenza virus A/Aichi/68 (H3N2) was given intramuscularly to a group of volunteers. The changes in serum haemagglutination-inhibiting (HI) and nasal wash neutralizing antibody were measured, and the results compared with that of volunteers given a TNBP-split vaccine containing 400 CCA of the same virus. More volunteers given the high-dose vaccine developed a fourfold rise in serum HI antibody, and there was a greater increase in geometric mean titre in this group. In addition, more volunteers given the high-dose vaccine developed detectable nasal wash neutralizing and anti-neuraminidase antibodies. Following low-dose vaccine, the production of nasal wash antibody was not related to the serum antibody response. For both groups given vaccine, antibody was detected most frequently in nasal washings with relatively high levels of protein and IgA; the concentration of IgA was also directly related to the protein concentration.

The production of neutralizing activity in serum and nasal secretion following immunization with influenza B virus.

Trials were made in volunteers in 1967 and 1968 of various virus vaccines against influenza virus B. Sera and serially collected nasal washings before and after immunization were tested respectively for haemagglutination-inhibiting and tissue culture virus-neutralizing antibodies to the same strain of influenza B/Eng/65 virus as that used in the vaccines. Infection, as determined by recovery of virus and serological changes following intranasal instillation of attenuated live virus, was accompanied by the subsequent appearance of neutralizing antibodies in nasal secretion. Inactivated vaccine subcutaneously did not evoke nasal antibody formation in 1967 but did so in 1968.In 1968 intranasal challenge of the volunteers with the attenuated virus 1 month after immunization demonstrated a correlation of susceptibility or resistance to infection with nasal and serum antibodies. Resistance appeared to depend either on a high level of serum antibodies or nasal antibodies, or both.

Adjuvant influenza vaccines.

Emulsified inactivated influenza vaccines have been in use for some 18 years and the goal of enhanced serological response lasting 2 years or more has been attained. The safety of the method in relation to immediate pyrogenic reactions has been demonstrated and no carcinogenic effects are known to have occurred in man. However, the problem of delayed local reactions after the injection of mineral-oil vaccines has not been solved. British experience of adverse reactions to commercial adjuvant influenza vaccine is quoted.New methods for obtaining adjuvant action without the risk of local abscess formation are needed both for inactivated whole virus and for split haemagglutinin vaccines. Reversal of water-in-mineral-oil emulsion to oil-in-water emulsion reduces viscosity and permits diffusion of the depot injection. A trial in Britain has shown equally good adjuvant properties of the reversed emulsion incorporating influenza virus vaccine so far as serological response is concerned, although it has not yet been conducted on a scale that would allow of adequate evaluation of the likelihood of delayed local reactions.