The faith of the cosponsors was rewarded. The day prior to opening, the conference reached its capacity of 300. Participants came from more than 30 US states and 19 foreign countries. Vaccines are a hot topic and getting hotter.
Keynote speaker Robert F. Breiman, MD, director of the national vaccine program office at the Centers for Disease Control and Prevention (CDC), provided a policy framework for the meeting. He described his job as "visualizing and making people understand the congruence between public health needs and the commercial market. It seems like it should be obvious, but it is not always recognized." He emphasized the need for planning by quoting that eminent philosopher of the diamond Lawrence "Yogi" Berra: "If you don't know where you are going, you might wind up someplace else."
Breiman said that the United States has licensed for production vaccines against 24 diseases, with two more likely this year. He called the Haemophilus influenzae b (Hib) vaccine "an amazing public health triumph. And it is one the public doesn't really appreciate because Hib really doesn't carry with it the same mark that polio or others did in earlier generations."
"Despite these incredible accomplishments, or perhaps because of them, the focus now has to come more on the risks of vaccines than on the benefits." Breiman attributed part of that shift to the quick response of the media and particularly the Internet. He called for increased attention to communicating the risks and the benefits of vaccines in educating both the general public and healthcare providers, as part of the total framework of vaccine development. Surveillance must also be strengthened "so that we can more precisely define vaccine-attributable adverse events risk and the effectiveness of vaccines once they are in use."
Within the United States, Breiman found "most frightening" the racial disparity that exists in terms of access to vaccination, particularly for pneumococcal vaccines. "African-Americans are at a much greater risk of incidence of pneumococcal disease and are much less likely to be vaccinated."
Breiman outlined principles for effective vaccine policy. They include laying out a plan that industry can support and, thus, be willing to invest and play its role in the process. He believes that the community can do more during the prelicensure phase "to more precisely define the risk of adverse events."
Ethical challenges must embrace how trials are conducted and how they are intended. "We need to test vaccines in settings where the disease magnitude is greatest, as well as offer to those locations the potential benefits once they are licensed," Breiman said. For some "limited use vaccines, like malaria," where there is limited market incentive in the developed nations, "we need to find a way to decrease the development risk for companies." He pointed to the increased global economy as a reason for national governments and international institutions, such as The World Bank, to contribute financial assistance to those efforts.
"Before it was, essentially, take a bacteria, kill it, inject it, and hope for the best," said Frederick R. Vogel, PhD, a senior scientist at the National Institute of Allergy and Infectious Diseases (NIAID), Division of AIDS. "Today we are moving away from the more empirical approaches of the past to more rational strategies of vaccine design based on recent advances in immunobiology. Rational vaccine design requires the identification of protection epitopes and the development of suitable formulations capable of driving protective immune responses to them."
Vogel explained that the highly purified antigens of modern vaccines are often "less immunogenic than many traditional vaccines." Adjuvants, or chemical helpers, can be used to help boost the immune response they generate. "Today there are hundreds of natural and synthetic compounds known to promote adjuvant activity. However, aluminum has remained the only adjuvant used in licensed vaccines in the United States."
"Adjuvants work by their ability to modulate the immune response to cytokines, their effects on T-helper subsets, and on antigen processing," Vogel said. They can push cells to either a TH1 or a TH2 response. By choosing the proper adjuvant it is possible to direct and optimize the immune responses that are appropriate for the vaccine. "If the vaccine is designed for cell-mediated responses, then you should use adjuvants that will push towards that."
Adjuvants have a role as a research tool. Vogel noted, "You might have the right antigen but if you don't drive it in the right way you won't necessarily see the protective immune response that you want. The advantage of using adjuvants with immune antigens is to drive the response in different directions to see which gives you the best protection."
Adjuvants can also help to reduce the number of antigens and/or the number of separate vaccinations required to achieve protection. That can help increase compliance with the proper schedule of serial vaccination and also reduce costs. Both are very important factors in any society, and they may become crucial ones in poorer nations.
Mark J. Newman, PhD, vice president of research and development at Vaxcell Inc, Norcross, Georgia, has been focusing on nonionic block copolymers. They are synthetic, stable, safe, and readily manufactured molecules commonly used in the pharmaceutical industry. Using different ratios of a polyoxypropylene (POP) core and polyoxyethylene (POE) ends, the company tried to drive TH1 and TH2 responses. "In the vaccine world it is fairly easy to get TH2 responses -- most of the adjuvants will do this," Newman said. "But the trick has been to induce TH1 responses."
By measuring the cytokines produced, Newman found that "copolymers with 10 percent POE significantly augmented type 2 helper T-lymphocyte responses," while a more hydrophobic product "with lower POE contents augmented both type 1 and type 2" responses. He is unsure how this works, but believes it is "by altering the way that the initial antigen is processed." This holds out the possibility of vaccines "customized by using adjuvant-active nonionic block copolymers that will augment the most appropriate types of immune responses."
Michel J. Caulfield, PhD, with Merck Research Laboratories, turned to the example of hepatitis B virus (HBV). Chronic carriers of HBV have elevated levels of alanine aminotransferase liver enzyme and continued evidence of HBV DNA in their blood. Although they develop antibodies to the core, they generally lack antibodies to the surface of the virus. They also have weak or poor cytotoxic T lymphocyte (CTL) reactions. By contrast, patients who have thrown off HBV carry antibodies to both the core and envelope. "They also develop fairly potent CTL responses," he said. "This raises the question, do chronic infections induce the wrong kind of response?"
"Our hypothesis is that chronic hepatitis B results from the induction of a weak immune response," said Caulfield. "A strong type 1 response may clear it after initial infection." However, current HBV vaccines are recombinants that induce a TH2 response and no CTL response or weak CTL response. They are useful for prophylaxis but not for therapy. Merck's goal is to develop a vaccine that will enhance the TH2 response.
Merck's strategy has been to formulate various DNA protein vaccine and adjuvant combinations, then measure and compare the IgG1 vs IgG2 responses they generate. Caulfield has found that calcium phosphate can act as an adjuvant for vaccine, "resulting in an approximately tenfold increase in antibody titers." Phosphorothioate oligodeoxynucleotide can enhance type 1 responses with protein vaccines through increasing IgG2 antibodies as well as CTL responses. Work continues toward fashioning a marketable product.
The clinical end point trial increasingly seems like an endangered species as medicine moves from short-term therapy to treating long-term chronic diseases. The accelerating pace of second and succeeding generations of innovation further outstrips the temporal capacity of traditional trials to provide answers. Researchers, manufacturers, and consumers are not content to wait years, perhaps decades, for the definitive word on life-saving or life-enhancing innovation. They want answers, and the sooner the better. A partial answer today often is more valuable than a more detailed answer next week.
Surrogate markers have become the new standard of evaluation of efficacy for accelerated approval by the US Food and Drug Administration. While they do not yet have the luster of the "gold standard" of double-blinded placebo-controlled clinical end point trials, they have acquired the patina of acknowledging real world practicalities in developing new medical technologies. Most conference participants acknowledged that surrogate markers are likely to be the standard by which improved variations and new combinations of vaccines will be evaluated.
Steven Black, MD, codirector of the Kaiser Permanente Vaccine Study Center in Oakland, California, posed the principal question of choosing surrogates: "Which is the appropriate correlate of protection: is it priming or is it circulating antibodies?"
It is an important question, because some vaccine combinations do not produce great amounts of circulating antibody but they do effectively prime the immune system to respond to the challenge of disease. Black said that vaccination can take seven to 14 days or longer to evoke an antibody response, but in a primed individual the response may be only 24 to 72 hours.
Black suggested that the answer might vary, depending on "the kinetics of onset of the infection. Where there is a long onset, such as with hepatitis B, priming might be perfectly adequate. Whereas another infection, where the onset is quite rapid, there might not be time for the primed individual to develop an antibody response, and circulating antibody might be more important."
This is only part of the story. David S. Krause, MD, a researcher with SmithKline Beecham Biologicals, reminded the audience, "Antibody concentrations alone do not convey information about cell-mediated immunity or other aspects of bioindividuality."
Krause turned to the efficacy trials of pertussis vaccines conducted by the National Institutes of Health (NIH) from 1994 to 1996. The trials concluded that "there was no specific correlate of protection. No specific antibody or combination of antibodies was found to be effective to predict protection." He summarized what is now accepted as surrogates for specific vaccines (Table 1).
|hepatitis B||pertussis||N. Meningitis B|
|diphtheria||Lyme||Hib - conjugate|
|N. Meningitis A.C.|
George R. Siber, MD, chief scientific officer of Wyeth-Lederle Vaccines and Pediatrics, argued that current surrogates are not reliably predictive for determining individual protection through vaccination. "One of the requirements to have a true surrogate for efficacy is that we need to know the effective mechanism of immunity against the organism. And we need to have an assay that reliably measures that protective antibody."
Siber explored the limitations of individual- and population-based correlates before making a pitch for "antibody concentration-specific protection." He described this method as not a simple yes-or-no but as a curve for calculating individual risk for developing infection at specific antibody concentrations, preferably measured shortly after immunization.
"If you have a curve relating titer with protection, you can estimate the protection of any new vaccine based on the distribution of antibodies that it induces that is different from the original vaccine." Siber cautioned that this modeling requires a large incidence of disease from which to calculate the curve; it will not work for relatively uncommon infections.
According to Siber, there are additional drawbacks. One is that "for many antigens, such as those for the pertussis vaccine, we don't have functional antibodies to measure." A second is unanswered questions about multiple protective antigens. And, what does one do when protection is influenced by cell-mediated mechanisms, where our assays are not as good? These appear to be the most crucial defenses with some types of infections.
John Clemens, MD, chief of the Epidemiology Branch at the National Institute of Child Health and Human Development, warned that "the idealized conditions of a phase III efficacy trial may lead us to overestimate vaccine impact." He pointed to pneumococcal vaccines and vaccines for measles as examples. However, it can also be true that exclusion of indirect impact "may lead us to underestimate not overestimate vaccines' impact. The major impact of PRP conjugate vaccines would never have been anticipated on the basis of phase III efficacy trials because those trials did not measure indirect effects." He urged effectiveness trials that more closely model real world conditions in which the vaccine is likely to be used.
Five new vaccines have been introduced in the United States since 1981, said Bruce Weniger, MD, assistant chief for vaccine development at the CDC. Two more seem likely to be approved shortly, and a handful of additions are likely within the next decade. "The challenge is, how are we ever going to incorporate all of these new vaccines into an increasingly crowded and complex immunization schedule?"
Weniger presented the current US schedule of recommended vaccinations to immunize a child (Table 2), which requires a minimum of 14 injections to take advantage of all newly licensed combination vaccines available today.
"As those of you who have accompanied your children to the doctor's office to receive injections already know, the principal problem is that shots are a terrifying and traumatic experience for many children." This can result in deferred or missed vaccinations.
One solution is to further combine several vaccines into a single inoculation. But as Weniger pointed out, "Chemical incompatibilities and immunology interference have made combination vaccines rather difficult to develop." Overlaying that are problems of the marketplace and antitrust regulation that may constrain companies from even discussing potential combinations. Oral and intranasal vaccines may represent a long-term option to some of these challenges.
Pearay L. Ogra, MD, chairman of the Department of Pediatrics at the University of Texas Medical Branch, Galveston, discussed mucosal administration of vaccine antigens. He explained how there are localized induction sites in lymphoid tissue where CD4 and CD8 cells expand in reaction to the vaccine. After activation, "the antigen peptides migrate to the infection sites where they perform their function in terms of antibody production and subsequent interaction with the antigens."
Research, Ogra said, "suggests that there is a certain degree of compartmentalization between the different induction sites. There can be local immunization response, but not a response that migrates into the lymphocytes." Immunization at a specific site may offer particular protections and weaknesses that differ from those obtained through immunization at another site. He noted that "animals immunized internasally had 100 percent protection in both the nose and lung." And "animals immunized in the intestine had 100 percent protection in the lung," but virtually all of them could be infected through nasal mucosal tissue.
"One can predict," said Ogra, "that if you put antigen in the mucus membranes in the inductor sites, you will induce antigen-mediated activation of many of these antigenated cells, which will migrate to distant mucosal sites. But then if you go back and boost them with antigens at the local sites, one would expect significant proliferation and further differentiation of these cells to produce a more profound response at the site of immunization" (Figure 1).
The strategy for immunization will depend on whether one wishes to prevent infection or prevent disease at a specific site. In a separate discussion, Ogra used the example of chlamydia. "If one wants to immunize the genital tract, but not necessarily put the antigen in the vagina, you can use the nose. Put the antigen there and then hope that if they get exposed under natural circumstances, at the time of infection you will be able to boost the response in the genital tract. So you may have mild infection but you won't have the disease."
Ogra suggested that one effective strategy for immunization might be "to prime internasally or by oral administration, then try to boost it by a little pill. One might see a more effective response than simply immunization of the inductive sites."
Robert B. Belshe, MD, director, Division of Infectious Diseases, Department of Medicine, St. Louis University School of Medicine, presented data on a clinical trial using a nasal spray to vaccinate for influenza.1 The randomized double-blind placebo-controlled trial enrolled 1602 children ages 15 to 71 months during the winter of 1996-1997. It tested the efficacy of one- and two-dose regimens.
The trial used a cold-attenuated influenza virus that is temperature sensitive. "The live vaccine attaches to the target tissue, the nasal mucosa, and replicates and stimulates the full complement of immune responses, antibody, and probably also cellular immune responses," Belshe said. It will reproduce in the nasal passages, which are about 25°C, but not in the lungs, which are about 37°C.
The spray produced the same degree of immunization as did drops when used in young children. "The advantage is that you do not need any cooperation at all from the kid," Belshe said. "They don't cry, there is no needle, it is done very, very quickly. So the simplicity of this device is really terrific." Adults are handed the device and use it themselves.
The study found that the vaccine was accepted, well tolerated, and effective against influenza. Only 14 of the 1070 vaccinated children developed culture-positive influenza, while 95 of the remaining 532 experienced that illness. "There was a 35 percent reduction in antibiotic use among the vaccinated children compared to the placebo group, if they had a febrile illness," Belshe said. "Clearly that is a dramatic reduction."
The live vaccine viruses "emerge from children, but these do not spread to contacted children," Belshe said. Nor does it appear to spread in very close quarters such as a day care setting. Data are being analyzed from a follow-up trial conducted during the 1997-1998 influenza season.
Weniger said that there should be no risk to healthcare workers exposed to the aerosol of the initial nasal application.
The nasal applicator comes prepackaged and loaded and is frozen until use. "I can foresee the day," Belshe said, "when this is over the counter and sold next to ice cream in the frozen food section. But that is a long way from now."
Vaccination and pediatrics are twins joined at the hip, so intertwined that we sometimes lose sight of the yeoman work of the former, and focus on vaccination primarily in terms of the unanswered questions before us rather than the ones that have been answered and have become routine practice.
Most vaccination does in fact occur during early childhood and provides lifelong immunity. It works, so we forget about it. However, there is a window of vulnerability during the first months, even year, of life. Attempts at inducing early protection by immunizing newborns have been generally disappointing, said Pamela M. McInnes, DDS, chief of the Respiratory Diseases Branch at NIAID. That is because the neonate's immature immune system often does not respond well to the vaccine challenge, or the immune response requires time to develop, during which the newborn is unprotected. The growing number of vaccines that must be accommodated further complicates the picture.
Recently, interest has focused on a strategy of passive transfer of antibodies in utero through vaccination of the pregnant mother. Some developing countries have tried it with tetanus toxoid and have reduced neonatal mortality for the disease by about one third.
NIAID is investigating the approach for group B streptococci, pneumococci, Bordetella pertussis, and respiratory viruses such as influenza and respiratory syncytial virus. The advantages of such a strategy are numerous, explained McInnes. "Young infants are vulnerable to numerous infections but they are least responsive to active immunization. Pregnant women do have access to healthcare and they do respond well to vaccines.
IgG antibodies cross the placenta well during the third trimester. And the benefit could be experienced by both the mother and offspring." Immunizing the mother will also eliminate her as a possible source of infection of her child.
McInnes continued, "In theory, one could harness the immune system and increase the number of doses needed for active immunization of the offspring. And depending on the disease, it might even be possible to avoid active immunization of the infant at all."
Richard A. Insel, MD, director of the Strong Children's Research Center at the University of Rochester School of Medicine, said that "at times the antibody response in pregnant women exceeds that of the nonpregnant state."
Insel reported that the interval between vaccination of the mother with tetanus toxoid and Hib is crucial. Inoculating with the second vaccine during the window of two to seven weeks following the initial vaccination resulted in "inhibition of the antibody response to the tetanus conjugate vaccine." From week eight forward there was no problem because the immune response had matured sufficiently.
Insel explained that the placenta thins out and becomes more permeable as it enlarges. "This explains why IgG is transferred so much better in the third trimester than it is in the second trimester of pregnancy." Thus, staging is very important; there is only a limited window of opportunity in which to most successfully intervene.
"There is a finite period, an interval that must occur, between immunization and the time that antibody can be transferred through the placenta to the fetus," Insel continued. "This interval reflects the time required to mount an antibody response in the system, and in addition it reflects the time that it requires for that IgG antibody that is induced to equilibrate with the larger total pool of IgG. In general, one recommends an interval of four to six weeks between immunization and delivery, if at all possible."
Insel cited the work of Englund et al, in which they compared the time between immunization of mothers and their deliveries.2 What they found was that "if the interval was greater than one month, 75 percent of maternal IgG1 antibody levels were transferred from mother to baby. In contrast, if the interval was only one to two weeks, the number was only 15 percent. So the extra two weeks resulted in a fivefold greater transfer of antibody."
Insel noted that the World Health Organization has established standards for vaccination of pregnant women. If the mother has not been immunized for tetanus, it recommends that she receive two immunizations, the first at least 50 days prior and the second at least 20 days prior to delivery.
"The half-life of an IgG antibody is approximately 30 days," Insel said. "So as long as a protective titer is induced [in the fetus], and it is several half-lives greater than protection, one can have prolonged levels of protective antibody in the newborn" for as long as six months after birth.
Insel said that it might be possible for maternal immunization to "prime" the neonate for future immunization. However, it also may be possible that maternal antibodies suppress neonatal responses. "One cannot walk away from this with any definitive data." The answer may well lie in the variable genetic immunocompatibilities of individual mothers and fetuses.
Nutrition may be an important factor in the development of immune response with some vaccines, said Ranjit Kumar Chandra, MD, director of immunology at Memorial University of Newfoundland, Canada. Much of the early work in the field has been done with young children in developing countries, and "many of those results can be extrapolated to developing countries."
Nutrition, Chandra said, "makes no difference with [levels of antigen response with] tetanus toxoid and pneumococcal vaccines, but it does make some difference in responses to adenovirus and hepatitis B vaccines. There is no work at all on the effect of nutrition on protective efficacy on vaccines in humans."
Chandra summarized his work on how poor nutrition can reduce immune response.3 It can reduce the production of T-helper cells, the proliferation of antigens and maturation of cells, receptor sensitivity and binding, and the production of cytokines.
"If a nutrient is essential for immune response, it does not mean that more of it is even better." The example Chandra used was his small study of 11 medical students who were given 150 mg/d of zinc. "Within four to six weeks we saw a very significant drop in lymphocyte responses and in parasitic responses. It took several weeks of stopping the supplement before this response came back to normal."
"Is immunologic decline an inevitable part of aging?" Chandra asked. "Does it occur in everybody?" He noted that there is a decline in physiological functions between the ages of 30 and 80. However, that is on the average; some people do not experience significant decline while others exhibit severe decline.
Chandra examined the immune response curves of two groups: one composed of people ages 20 to 40 years and a second of people ages 80 to 100 years. He found that in the upper quartile of both groups, "12 percent had two or more nutrient deficiencies. The lowest quartile was 47 percent." While this does not prove causation, "it suggests that there may be some effect of nutrition on immune response."
Chandra asked a second question: if we improve nutritional deficiencies in the elderly, will it lead to improved immune response as it does in the young? He acknowledged studies showing the positive effect of regular exercise on the immune system and the negative effect of bereavement, which complicates teasing out the effect of nutrition.
Then he turned to a study by Meydani et al, which used 50, 200, and 800 mg doses of vitamin E supplement over an eight-month trial.4 All three dosage groups showed a significantly increased sensitivity to antibodies and to hepatitis B vaccine. But the response did not correlate with dose. All that was necessary was compensation for insufficient vitamin E. A significantly higher dose may in fact produce poorer results.
"There is always an upper threshold beyond which you will see a decline in immune response," said Chandra. "If you take more than 2 g/d of vitamin C, which is a massive dose, you do begin to see a decline in immune responses." He knows of two or three unpublished trials that used large amounts of zinc in cancer patients and showed "a very profound adverse effect of 100 mg. So one has to be careful" about large doses of any supplement.
Deficiencies are seldom limited to a single nutrient. Thirty-five percent of people in the industrialized world "have deficiencies in two or more vitamins or nutrients," Chandra said. He set out to formulate the ultimate supplemental regimen. He began with values "very close to the recommended dietary amounts. So that if you use them in addition to what you are taking in in the diet, at the most what you are taking in is two times the recommended daily allowance." Then the laboratory established dose-response curves for each supplement to find out which produced the highest immune response. Finally, he calibrated the package of supplements to maximize the total immune response.
Chandra wanted to know what type of clinical effect this package might have. He asked, "If we do improve nutrition and immunity, will it result in an overall reduction in illness?" He conducted a randomized placebo-controlled study in 96 seniors whose average age was 74. "There was almost a 50 percent reduction in common infections in the supplemental group." He concluded that "for every dollar spent on dietary counseling or nutritional supplements, you will save approximately $28 in healthcare cost for infectious disease." He saw the most important impact of nutrition as not necessarily on the prolongation of life but on the process of healthy aging -- living a better quality life less marred by infection.
A preventative vaccine for HIV is undisputedly the most pressing challenge before the fraternity of vaccinologists. In May 1997 President Clinton set a goal of finding that vaccine within ten years. David Baltimore, MD, already had been appointed to chair the AIDS Vaccine Research Committee at the NIH. However, a faction of scientists has chafed under Baltimore's leadership of that effort.
Weniger made a foray at the March 1998 meeting of the Presidential Advisory Council on HIV/AIDS (PACHA), of which he is a member. He invited the late Jonathan Mann, MD, MPH, dean of the Allegheny University School of Public Health in Philadelphia, to speak before PACHA's international committee.
In discussions at the PACHA meeting, Mann and Weniger both made tarter comments. "I've been utterly amazed by the paralysis -- there is just no other word -- and the failure of vaccine development," said Mann. "David Baltimore is not equipped to make tremendous contributions to vaccine development."
Weniger charged that the current vaccine effort has been a failure. He proposed strong language for PACHA to adopt but was unable to gain a single vote of support.
The issue arose again at the Vaccine Conference, this time from the late Mary Lou Clements-Mann, MD, a professor at the Center for Immunization Research at Johns Hopkins University and spouse to the aforementioned Mann. She chose to focus on two issues of "why a milestone-driven strategic process for an AIDS vaccine has not yet emerged."
"The first major misconceptions are that vaccines are expected to provide sterilizing immunity, in other words, to completely prevent infection," Clements-Mann said. "Rather, the goals for public health importance have been to provide sufficient immunity to prevent or ameliorate severe disease. Few vaccines completely prevent infection." She cited the inactivated polio vaccine as an example.
Clements-Mann added, "Another misconception is that vaccine protection must be demonstrated in animal models prior to conducting efficacy trials in humans." She said that historically results of vaccine trials in animal models often showed data significantly different from trials in humans.
Clements-Mann attacked "the notion that correlates of protective immunity must be known prior to conducting efficacy trials based in humans," saying that was impossible to know ahead of time. Furthermore, early field trials are likely to provide information useful for refining later generations of vaccine.
A feeling of discontent grew among many during Clements-Mann's presentation and erupted during the question period. "What is the biologic plausibility or hypothesis that you are trying to test with such a trial?" asked one participant from the floor. "There has to be something from the phase I and phase II trials that looks promising. I hope that we are gleaning something from that before we go into a field trial."
Clements-Mann did not respond directly to the question. She pointed to the need for a vaccine throughout the world, the willingness of people to participate in such a trial, and the inability to do challenge trials during phase II study. She said that her purpose was to talk about the process rather than individual vaccine options.
"No one has demonstrated that the types of immune responses clearly do something to the pathogen that people will see," said one questioner. "I think that is the fundamental reason why these trials have not gone forward."
Near the end of the conference, co-organizer Bruce Weniger declared it a success. The second annual conference will take place March 28-30, 1999, in Bethesda, Maryland.
U.S., January-December 1998
|Vaccine||Birth||1 Mo.||2 Mos.||4 Mos.||6 Mos.||12 Mos.||15 Mos.||18 Mos.||4-6 Yrs.||11-12 Yrs.||14-16 Yrs.|
|Hep B-2||Hep B-3||Hep B|
|Diphtheria and tetanus toixoids and pertussis||DTaP or DTP||DTaP or DTP||DTaP or DTP||DTaP or DTP||DTaP or DTP||Td|
|Haemophilus influenzae type b||Hib||Hib||Hib||Hib|
|Range of acceptable ages for vaccination|
|Vaccines to be assessed and administered if necessary|
Bob Roehr is a medical writer based in Washington, DC (e-mail: firstname.lastname@example.org).
1. Belshe RB. The efficacy of live-attenuated, cold-adapted, trivalent, intranasal influenza virus vaccine in children. N Engl J Med 1998; 338:1405-1412.
2. Englund JA, Glezen WP, Thompson C, et al. Haemophilus influenzae type b- specific antibody in infants after maternal immunization. Pediatr Infect Dis J 1997;16:1122-1130.
3. Chandra R. Graying of the immune system: can nutrient supplements improve immunity in the elderly? JAMA 1997;277:1398-1399.
4. Meydani SN, Meydani M, Blumberg JB, et al. Vitamin E supplementation and in vivo immune response in healthy elderly subjects: a randomized controlled trial. JAMA 1997;227:1380-1386.
5. Mann JM. Paralysis in AIDS vaccine development violates ethical principles and human rights. JIAPAC 1998;4(5):42-44.