Improbability of effective vaccination against human immunodeficiency virus because of its intracellular transmission and rectal portal of entry.

The worldwide effort to produce a vaccine against AIDS continues to disregard the fact that even human immunodeficiency virus (HIV)-specific neutralizing antibodies and cell-mediated immunity are ineffective against virus within cells without viral antigens on the cell membrane--and that much of HIV infection is transmitted in this manner. According to a recent report, a simian immunodeficiency virus vaccine that protected monkeys against an intravenous challenge with cell-free virus was, as predicted, ineffective against an intravenous challenge with the same amount of virus in infected cells. Moreover, antibody and HIV have been found to coexist in cell-free plasma from asymptomatic and symptomatic patients. Excluding direct introduction of HIV into the blood-stream, the most common and efficient form of transmission of HIV infection is by receptive anal intercourse, and semen contains large numbers of infected cells per milliliter. Recent reports showing that colorectal cells can be persistently infected by HIV and that HIV RNA and cDNA are present in the cells of the colon of dead AIDS patients indicate that either cell-free or intracellular HIV has the capacity to multiply at the portal of entry in the colorectal area without interference from neutralizing antibodies. The available data provide no basis for testing any HIV vaccine in human beings either before or after infection. The main challenge is to find a way to kill cells with chromosomally integrated HIV cDNA without harming normal cells, perhaps by identifying repressor proteins that might be produced by the cells with integrated HIV cDNA and thus could become specific targets for cell-killing drugs.

Perspectives on rapid elimination and ultimate global eradication of paralytic poliomyelitis caused by polioviruses.

Poliomyelitis caused by polioviruses has already been eradicated from industrialized countries of North America, Europe, Asia and Oceania, but the procedures by which this eradication was achieved are not adequate for the poor tropical and subtropical countries. The major challenge now is first to eliminate it rapidly from Asia and Africa where an estimated 250,000 cases and 25,000 deaths currently occur annually. The great progress toward eradication of "wild" polioviruses from poor tropical and subtropical countries in Latin America was achieved not by the procedures still recommended by the WHO Expanded Program on Immunization (EPI) but by the independently organized annual, national days of antipolio vaccination - all based on the use of large armies of well-trained non-professional, community volunteers - first used in Cuba (1962), Brazil (1980), Nicaragua (1981), Dominican Republic (1983), Paraguay (1985), and Mexico (1986). This novel approach, described in some detail in this communication, is recommended for the rapid elimination of wild polioviruses from Asia and Africa, and for ultimate global eradication with the help of a special cadre within the EPI of WHO. The extensive use by the Pan American Health Organization (PAHO) of highly sophisticated regional virus laboratories has led to the recognition that, in areas from which poliomyelitis caused by polioviruses has been largely eliminated, there are thousands of cases of acute flaccid paralysis, previously clinically diagnosed as "probable poliomyelitis", that have no viral etiology, a phenomenon previously reported by Dr. Manuel Ramos Alvarez in Mexico City in 1967.

PIP: Paralytic poliomyelitis caused by the poliovirus has been almost completely eradicated in many countries. This was achieved by a maximal break in the chain of transmission through mass vaccinations. Strategies in the poor subtropical and tropical climates of Asia and Africa where annual estimates of paralysis are 250,000 cases must be adapted to countries characterized as having year-round fecal born infectious agents, including paralyzing polioviruses and other enteric viruses, and inadequate health facilities, poor sanitation and hygiene, and high levels of poverty. A virologic study in Mexico City and the Soviet experience lead to the successful Cuban strategy in 1962 of 2 annual, national days (2 months apart) of mass administration of OPV to all children in a specified age group, regardless of how many doses of OPV already had been received. The implementation by independently organized well-trained nonprofessional community volunteers is provided in detail. It is this strategy that is recommended for a WHO EPI group and Pan American Health Organization effort to eradicate poliomyelitis worldwide. The discussion of the worldwide effort to eradicate smallpox points out that the methods, used for smallpox eradication would be ineffective because poliomyelitis infections are clinically inapparent and vaccination around recognized cases is insufficient to break the chain of transmission. Problems arise due to the misdiagnosis of acute paralytic diseases which pathologically are not poliomyelitis. The distinction between paralytic poliomyelitis caused by polioviruses and paralytic poliomyelitis is made and discussed. The experiences of eradicating paralytic poliomyelitis in economically developed, temperate climate countries and rapid elimination in underdeveloped subtropical and tropical countries is described in some detail. The OPV programs and lessons learned in Cuba (1962), Brazil (1980), the Dominican Republic (1983), Nicaragua (1981), Paraguay (1985), and Mexico (1986) are included. Inadequate mass campaigns which did not work to break the chain of wild polioviruses but reduced the disease level were Columbia (1984), El Salvador (1985), and Turkey (1985). Measures of achievement in Latin American are identified, and recommendations for worldwide eradication are given.

Measles, killer of millions in developing countries: strategy for rapid elimination and continuing control.

Measles, which is still killing about two million children a year in poor countries, was mostly eliminated within two to three months after the conclusion of a special, national mass vaccination campaign in which all children of a selected age group received measles vaccine subcutaneously during a period of days to months, regardless of a history of previous vaccination or measles. This strategy was tested in the Dominican Republic in 1985, in Cuba in 1986-87, and in the State of São Paulo, Brazil May 11-June 10, 1987. Subsequent control was maintained by different procedures in the three states. A simple, rapid indirect immunofluorescent test for IgM measles antibody, used in Greater São Paulo, was more efficient in confirming concurrent infection with measles virus than the hemagglutination inhibition test for IgG antibody, and only one blood specimen taken during the course of the rash was needed to confirm the etiologic diagnosis in 97.5% of 240 cases confirmed by IgM. In Greater São Paulo and Cuba, it was found that over 90% of the small number of suspect measles cases reported during the first year after the mass campaign, were not caused by measles virus. The cost of disposable syringes and needles in the State of São Paulo, where 8,565,230 children were vaccinated in 10,527 centers in 30 days, was U.S. $2,057,753 or 63% of the total. Immunization by aerosol could have vaccinated this number of children more easily and effectively in one day if each of the vaccination centers had been supplied with one plastic foot or hand pressure pump and nebulizer at a cost of only about U.S. $300,000.

Strategy for rapid elimination and continuing control of poliomyelitis and other vaccine preventable diseases of children in developing countries.

Estimates of a recent yearly incidence of 400 000 cases of paralytic poliomyelitis, 2.5 million deaths from measles and its complications, over 1 million deaths from neonatal tetanus, and 735 000 deaths from pertussis in Asia, Africa, and Latin America now pose a greater challenge for new action than did the worldwide eradication of smallpox several years ago. By virtue of the conditions obtaining in the developing countries mere expansion or acceleration of what is being done now--even with modifications that may achieve a temporary increase in vaccine coverage--cannot achieve the desired rapid elimination and continuing control of these diseases. A new strategy--namely, bringing the vaccine to the people during annual national days of vaccination--has already been used successfully in some small and large developing countries of Latin America for the rapid elimination and continuing control of polio. This strategy could be adapted to include vaccination against measles, pertussis, and neonatal tetanus by additional training of community volunteers in the large auxiliary health armies that work with the existing health services each year.

High effectiveness of aerosolized chick embryo fibroblast measles vaccine in seven-month-old and older infants.

Neither the presence of hypertonic sugar nor the absence of 1% human albumin in the aerosolized chick embryo fibroblast (CEF) measles vaccine was previously found to be responsible for its inadequacy in infants with titers of maternal plaque-neutralizing (PN) antibody at which human diploid cell measles vaccine was immunogenic. Eight weeks after administration of CEF measles vaccine containing 1% human albumin, antibody had developed in all 10 infants 7-10 months old and all 11 children 12-35 months old but in only 26% of 23 infants 3-5 months old and 67% of 9 infants 6 months of age. Failure of antibody development was associated with prevaccination PN antibody titers of greater than or equal to 1:50 (with one exception at a titer of 1:25). The PN antibody response to CEF vaccine (diluted 1:10, approximately 10(5) pfu/ml) in infants under seven months of age (geometric mean titer [GMT], 1:421) was significantly lower (P less than .005) than in older infants (GMT, 1:1,564). At a 1:1,000 dilution of vaccine, only 50% of 10 infants 13-25 months old, 20% of 15 infants 7-10 months old, and none of 8 infants 6 months old developed antibody.

Oral poliovirus vaccine: history of its development and use and current challenge to eliminate poliomyelitis from the world.

Oral poliovirus vaccine (OPV) is like no other live virus vaccine used in humans: vaccine strains multiply extensively in the intestinal tract, are widely disseminated in the family and community, and immunize a large proportion of the unvaccinated population. During the search for optimal strains for vaccine use, motor neurons in the spinal cord of chimpanzees (and by extrapolation those of humans) were found to be much more resistant to polioviruses than those of monkeys; the reverse was true for the alimentary tract. Various biologic properties of polioviruses also varied quantitatively over a wide spectrum and were genetically distinct. The phenomenon of somewhat increased neurovirulence for monkeys, but not for chimpanzees, encountered in excreted virus was extensively studied in families, in children's homes, and finally among hundreds of thousands of susceptible children and adults in areas where only 50% of the susceptible population received OPV; these studies did not reveal evidence of danger. During the past 20 years approximately 5 million cases of paralytic poliomyelitis were probably prevented by OPV in predominantly temperate-climate countries inhabited by approximately 2 billion people. OPV has also been used less extensively and not optimally in many tropical and subtropical countries, where paralytic poliomyelitis is now known to be an important public health problem, with reduction in numbers of cases but not elimination of the disease except in some countries with better health services. Experience in Cuba during the past 21 years, in Brazil during the past 5 years, and in the Dominican Republic during the past 2 years has shown that the strategy of annual short-term vaccination of all children in the most susceptible age groups can rapidly eliminate the disease from tropical and subtropical countries.

Successful immunization of infants with and without maternal antibody by aerosolized measles vaccine. II. Vaccine comparisons and evidence for multiple antibody response.

In 4- and 5-month-old infants in whom the undiluted chick embryo fibroblast (CEF) Schwarz strain measles vaccine had a poor immunogenic effect, there was an increase in immunogenicity when the high sugar concentration was diminished without reference to added albumin. The human diploid cell (HDC) measles vaccine was still superior in this age group even in a lower concentration of the Ikic, Edmonston-Zagreb strain of virus. More aerosolized, HDC Ikic strain virus was required for high seroconversion rates in 4- and 5-month-old infants who had higher titers of prevaccination plaque-neutralizing (PN) antibodies. Some of these infants had a delayed immune response that was absent at six weeks but present at three months after vaccination. The data provided evidence that the PN and enzyme-linked immunosorbent assay techniques measured different antibodies that develop and persist in different ways in 4- to 5-month-old infants. The HDC lyophilized measles vaccine yielded unexpectedly high seroconversion rates after subcutaneous injection of 5,000 plaque-forming units (PFUs) in 4-, 5-, and 6-month-old infants: 69%, 89%, and 100% respectively, at 14 weeks. In 12- to 23-month-old infants there was seroconversion of 92% and 100% at six weeks after inhalation of an estimated 175 PFUs of the CEF vaccine and 375 PFUs of the HDC vaccine, respectively. Within six weeks after vaccination, the PN antibody titers were significantly higher with the CEF vaccine (geometric mean titer of 2,275) than with the HDC vaccine (geometric mean titer of 343).

Strategies for elimination of poliomyelitis in different parts of the world with use of oral poliovirus vaccine.

Since its first mass use in 1960, oral polio vaccine ( OPV ) has largely eliminated paralytic poliomyelitis from temperate-climate and subtropical regions of the world that have good health services and a combined total population of almost 2,000 million people. The various strategies used in these countries have been highly successful even where, as in the USA, large numbers of children received no vaccine or only a single dose of OPV . During the period of 1981-1982, only 2.8 cases per 100 million total population per year were reported in the USA. The main challenge in the present era is the economically undeveloped tropical and subtropical regions with inadequate health services that are inhabited by more than half of the world population, where recent surveys for residual paralysis due to poliomyelitis have shown that the incidence of the disease has been higher than it was in the USA and other predominantly temperate-climate countries before the vaccine era. The problem in these countries is that the majority of children receive no vaccine and that the extensive year-round dissemination of virulent polioviruses requires a different strategy of vaccination from that used in the temperate-climate countries. The special point about the annual mass vaccinations with OPV for all children younger than three, four, or five years of age-which have proven highly successful in Cuba (for the past 20 years), in Brazil (during the past three years), and recently also in Mexico-is that all the children are usually vaccinated within one or two days, which quickly breaks the chain of transmission of the virulent viruses, and the annual campaigns create and maintain the maximum number of children with resistant intestinal tracts.