The Sabin live poliovirus vaccination trials in the USSR, 1959.

Widespread use of the Sabin live attenuated poliovirus vaccine has had tremendous impact on the disease worldwide, virtually eliminating it from a number of countries, including the United States. Early proof of its safety and effectiveness was presented in 1959 by Russian investigators, who had staged massive trials in the USSR, involving millions of children. Their positive results were at first viewed in the United States and elsewhere with some skepticism, but the World Health Organization favored proceeding with large-scale trials, and responded to the claims made by Russian scientists by sending a representative to the USSR to review in detail the design and execution of the vaccine programs and the reliability of their results. The report that followed was a positive endorsement of the findings and contributed to the acceptance of the Sabin vaccine in the United States, where it has been the polio vaccine of choice since the mid-1960s.

The poliomyelitis story: a scientific hegira.

There is evidence that paralytic poliomyelitis occurred in ancient times, but it was not recognized as a distinct disease until the eighteenth century and did not come into prominence until the late nineteenth century when epidemics began to appear. Outbreaks of increasing size were reported first in the Scandinavian countries, then in the United States and elsewhere, to the surprise and consternation of the medical profession. Poliovirus was first isolated in 1908, but many years of intensive research were required before the epidemiology and pathogenesis of the disease were sufficiently understood to allow preventive measures to be devised. The road to eventual success was complicated by controversies, setbacks, and tragedies, played out and influenced by many powerful personalities. Today there are two effective vaccines. The disease has been virtually eliminated in countries where they have been used extensively, yet in the developing areas of the world recent "lameness surveys" indicate that the incidence of paralytic poliomyelitis is as high as it was during the peak years in the United States in the early 1950s. The challenge now is to use the available vaccines to extend control to the developing countries and eventually to achieve elimination of the disease worldwide.

Persistence of vaccine-induced immune responses to rubella: comparison with natural infection.

Serologic responses and patterns of antibody persistence in children given HPV-77 DE-5 or RA27/3 vaccine were compared with those in children who had experienced natural infection. The results indicated that both vaccines induce long-lasting immunity in most individuals. RA27/3 vaccine proved more immunogenic and resulted in higher antibody titers; after 11 years 95% of those who seroconverted who were tested had hemagglutination-inhibiting (HAI) antibodies and 100% had neutralizing (NT) antibodies. Titers in HPV-77 DE-5 vaccinees were lower, and in 16% of those whose immune responses were feeble, HAI titers decreased to less than 1:8 after nine to 12 years; however, when their sera were examined by the more sensitive latex-agglutination test, all but two were found to have specific rubella antibody at levels of 1:1 to 1:16. Natural infection with wild virus was shown to induce more vigorous immune responses than did either vaccine: antibody titers were higher, decreases were smaller, and none fell to less than 1:8 (HAI) or less than 1:4 (NT).

Use of enzyme immunoassays and the latex agglutination test to measure the temporal appearance of immunoglobulin G and M antibodies after natural infection or immunization with rubella virus.

The time course of appearance of antibodies after infection with rubella virus was determined with an immunoglobulin G (IgG) detection enzyme-linked immunosorbent assay, a latex agglutination test, and an IgM detection enzyme-linked immunosorbent assay. In six naturally infected rubella patients and 26 vaccinees, antibodies measured by either the IgG enzyme-linked immunosorbent assay or the latex agglutination test generally appeared in parallel with those detected by the hemagglutination inhibition test. By 28 days after inoculation of live virus vaccine and by 2 days postonset of clinical rubella symptoms caused by natural infection, antibodies were found by the two tests for all individuals. A commercially available enzyme-linked immunosorbent assay kit was used to detect rubella-specific IgM. After natural infection, IgM appeared earlier than IgG, and although IgM titers decreased rapidly postinfection, in four of five patients antibodies were still detectable 40 to 43 days after the onset of clinical symptoms. After vaccine-induced infection, rubella-specific IgM was lower in titer than after natural infection and was detected in only three of seven vaccinees 70 days post-immunization.

Comparison of the latex agglutination test with the hemagglutination inhibition test, enzyme-linked immunosorbent assay, and neutralization test for detection of antibodies to rubella virus.

The ability of a rapid, latex agglutination test to diagnose rubella infection and to measure immune status was evaluated by comparison with the hemagglutination-inhibition (HAI) test, enzyme-linked immunosorbent assay (ELISA), and the neutralization (NT) test. The latex agglutination test accurately detected serological conversions in 74 pairs of sera representing 21 natural infections and 53 immunizations. The antibody levels of 276 sera from the general population were determined by latex agglutination, HAI, and ELISA. The correlation coefficients between the titers obtained by HAI and latex agglutination and by ELISA and latex agglutination were statistically significant. Results on 12 sera did not agree when measured by the three tests. These sera were included among the 196 specimens tested by NT. The correlation coefficient between NT and latex agglutination titers was statistically significant. There was one serum positive by latex agglutination but negative by NT, and five sera were negative by latex agglutination but had titers of 4 to 8 in the NT. The relative sensitivity of detecting antibody was greater by latex agglutination than by HAI. An additional 49 sera containing residual nonspecific hemagglutinin inhibitors were evaluated by latex agglutination and NT. The untreated sera showed no false positive reactions, and 36 of 39 NT positive sera were positive in the latex agglutination test.

Clinical, virologic, and serologic evidence of Epstein-Barr virus infection in association with childhood pneumonia.

To explore the association of Epstein-Barr virus infection with childhood pneumonia we studied two patients whose mononucleosis-like illnesses were accompanied by pneumonia; both had virologic and serologic evidence of current or recent EBV infection. We then analyzed the sera of 71 children (age range, 14 months to 9 years) with pulmonary infiltrates for the presence of four classes of antibody to EBV. Antibody responses consistent with current or recent EB virus infection were found in 15. Two children had IgM antibodies to the EBV viral antigen at titers greater than or equal to 1:160, indicating current infection, and all 15 patients had antibody to components of the early antigen complex, suggesting recent infection. A fourfold rise or drop in one or more EBV-specific antibody classes was noted in eight patients within 30 days following onset of clinical illness. Few patients had clinical features suggesting infectious mononucleosis. Eight of the 15 with serologic evidence of current or recent EBV infection also had clinical or serologic evidence of infection with another pathogen--bacterial, viral, or mycoplasmal. Thus, in childhood pneumonia, EBV may be a primary, co-primary, or secondary pathogen; it may be reactivated in the course of infection with another agent, or possibly, by suppressing immune function, it may precipitate infection with some other organism.

Neutralizing and hemagglutination-inhibiting antibodies to rubella virus as indicators of protective immunity in vaccinees and naturally immune individuals.

In general, hemagglutination-inhibiting (HAI) and neutralizing (NT) antibodies to rubella virus tend to parallel one another, and the presence of either antibody has been interpreted as reflecting protective immunity. It has recently been shown that persons who have HAI antibody but lack NT antibody may be subject to reinfection. In the present study these two antibodies were compared with regard to their appearance and persistence in vaccines and in those who have experienced natural infection. NT antibody appeared more slowly following immunization with HPV77DE5 or Cendehill vaccines than after natural infection or immunization with RA 27/3 vaccine. As with natural infection, initial NT antibody responses to RA 27/3 vaccine were of higher titer and persisted at higher levels for three years than was the case with either of the other vaccines. NT testing procedures were found to differ in sensitivity, depending on several factors including the cells in which the virus was grown.

Controlling rubella: problems and perspectives.

Long-term effectiveness of rubella vaccination in childhood is of particular importance because the ultimate goal of immunization is the prevention of infection during pregnancy. To determine how well vaccine-induced immunity persists in comparison to that acquired naturally, several hundred susceptible children who seroconverted after receiving HPV77DE5 vaccine were followed serologically over a 3-to-5-year period. The results indicate that vaccine-induced antibodies are less stable than those acquired through natural infection, and their persistence is closely related to the original response to immunization. Thus children who responded with a broad range of antibody types and who had brisk postvaccinal hemagglutination-inhibiting antibody titers of greater than or equal to 1:64, maintained such levels without significant decline. In contrast, among the children who had feeble hemagglutination-inhibiting antibody responses initially and failed to develop complement-fixing or precipitating antibodies, a significant proportion lost detectable hemagglutination-inhibiting antibody levels after 3 to 5 years. The current and future immunity of such children is therefore in doubt, unless natural reinfection with wild rubella virus or revaccination with a more effective vaccine corrects their antibody deficiencies.

The relationship of a newly described acute-phase protein to human gestation.

Rho is a newly described acute-phase serum protein which increases in titer in response to a variety of inflammatory and infectious diseases. It is present in 100 per cent of sera from pregnant women by the twentieth week of gestation, rises in titer until term, and then falls slowly during the postpartum period. It was barely detectable in some fetal sera and in some amniotic fluid samples near the end of the first half of gestation, and it could not be demonstrated in fetal tissue obtained at that time. Fetal serum titers increase with gestational age, but fetal levels remain below those of maternal sera. Undifferentiated placental tissue and estrogen/progestin do not appear to evoke rho antigen production. The stimulating mechanism during gestation remains unknown.

Large-scale production of rubella precipitinogens and their use in the diagnostic laboratory.

A method for producing large quantities of rubella theta and iota precipitating antigens in Vero cells is described. Using this reagent, the detection of anti-theta antibodies was found to be as sensitive as the hemagglutination inhibition test for both the determination of immune status and the diagnosis of acute rubella infection. The detection of anti-iota antibodies may permit diagnosis of rubella infection, when the collection of the first serum has been delayed and the early rise of hemagglutin-inhibiting and anti-theta antibodies has been missed.

Characterization of a human acute phase protein found in association with rubella virus infection.

A precipitating antigen, rho, was first detected in the blood of persons with rubella and in rubella virus-infected cell culture fluids (1). Partially purified antigens from both sources were examined and shown to have similar properties, although antigen from serum sedimented more heterogeneously, with estimated coefficients from 15 to 21 S, while that from culture fluids sedimented in the 11-14 S region. In each case, antigen was located in the beta-1 zone after electrophoresis in agarose, and at a density of 1.305 g/ml after centrifugation in CsCl. Stability characteristics were typical of protein antigens. Immunofluorescent microscopy revealed that rubella virus induced the appearance of rho antigen scattered throughout the cytoplasm of infected cells. When cells containing antigen were exposed for 24 h to 5 microg/ml actinomycin D rho was no longer detectable, indicating the probable cellular origin of the antigen. Also, titers in medium of infected cultures showed a reduction after actinomycin treatment, but levels of the virus-specified antigen, iota, were relatively unaffected. Rho appears to be a protein common to man and many animals. In vitro, it was induced by rubella virus and by adenovirus. In vivo, rho titers were shown to be elevated after rubella virus infection and, to a lesser extent, after infection with certain other viruses. High titers were also demonstrated in women late in pregnancy and in patients with rheumatoid arthritis. In man and the chimpanzee, the appearance and decline of rho in the blood after rubella virus infection were temporally similar to the patterns of CRP, although rho seemed to be a more sensitive indicator of infection. The data presented indicate that rho is a newly recognized acute phase protein inducible by certain virus infections and by other unidentified stimuli present prominently in pregnancy and rheumatoid arthritis.