Abstract
Vaccinations have had tremendous success in the 20th century. However, in the 21st century, we are facing complex immunological issues in relation to controlling underlying infectious diseases. Therefore, new technologies are needed to develop vaccines against infectious diseases like respiratory syncytial virus, human immunodeficiency virus, and cytomegalovirus. In addition, recent emerging infections have taught us that we must prepare preventative measures in advance using our scientific abilities.
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In recent years, new strategies have been incorporated into live vaccine development, including reverse genetics (20), reverse vaccinology (25), deletion mutants (14), and codon change (15), and most frequently harmless vectors expressing genes coding for protective proteins. In addition, DNA plasmids (8) and RNA (messenger or self-amplifying) (7,17) have shown their ability to express important molecules.
Despite these successes, we have no vaccines for a long list of pathogens shown in Table 2. For each of those a vaccine would be useful and in some cases could prevent highly prevalent diseases. In addition, some of the older vaccines need improvement and even replacement. I will briefly discuss a limited number of areas that have not yet yielded perfect vaccines.
SARS, severe acute respiratory syndrome.
Respiratory syncytial virus (RSV) causes the most important infection of infancy and has long resisted effective vaccine development owing both to safety issues and to poor immunogenicity of candidate fusion (F) protein preparations. The discovery of more immunogenic prefusion forms of the F protein has raised hopes, as have new attenuated strains that might be used in infants (9). Perhaps even more promising in the near future is using F protein to immunize pregnant women to provide passive immunity to their infants and to immunize the elderly against reinfection with RSV.
Pertussis had been relatively well controlled through the use of whole cell inactivated vaccines, but reactions to those vaccines were problematic. The development of acellular vaccines containing one to five antigens of Bordetella pertussis eliminated those reactions but diminished efficacy in the long term. While efficacy of acellular vaccines was satisfactory over the first 2 years postvaccination, it faded thereafter owing to the Th2 orientation given to infants by the first doses. Moreover, formol inactivation of pertussis toxin destroyed important epitopes. Many improvements of acellular vaccines are being discussed, the most simple of which is the substitution of genetically inactivated pertussis toxin. Stronger adjuvants and inclusion of additional virulence factors are also under study (19).
The two major attenuated rotavirus vaccines and their copies have had spectacular success in high income countries in reducing infantile diarrhea and dehydration. Even in low- and middle-income countries their success has reduced morbidity and mortality, but percentage efficacy has been considerably lower in those countries (10,28). The reasons for lower efficacy in poor countries are many, including concomitant ingestion of breast milk, passively transferred maternal antibodies, interference by simultaneously administered oral polio vaccine, and morphological changes in the intestinal mucosa caused by other pathogens. However, the major reason seems to be influence of the microbiome on replication of the vaccine viruses (11). The presence of Bacteroides species in the intestine seems to lower the efficacy of rotavirus vaccines.
No other vaccine is recommended for all ages more than influenza vaccine. However, if we are honest, the efficacy of our current vaccines is only moderate at best, while often it is poor (5). In my opinion, the principal reasons are that the titer of hemagglutination-inhibition antibodies is often insufficient and that strain variation in the hemagglutinin (HA) prevents high efficacy. Increasing the dose of HA and using stronger adjuvants have both been shown to increase efficacy (6,27). However, there is also an important focus on adding new antigens to influenza vaccine, the most prominent being the so-called stem antigen that might give breadth of strain protection (16), as well as neuraminidase and the M2e antigen (4).
What about vaccines needed for the future? Space does not allow discussion of all of the pathogens in Table 2, so I will confine myself to a selected few.
The human cytomegalovirus (CMV) is a ubiquitous infection. Its pathogenicity in adults is certainly obvious in transplant patients and it may be responsible as a synergistic factor in other pathologies like immunosenescence. However, its role as the most important infectious cause of birth defects is unquestionable. Efforts to develop a vaccine against CMV have been going on since the 1970s, with partial success and ongoing developments (1,22). It was shown early on that vaccination with an attenuated strain of CMV and with the subunit gB surface protein of the virus could protect solid organ transplant recipients against the virus carried within the donor organ. A study using a DNA plasmid coding for a CMV tegument protein that stimulates cellular immunity is currently being conducted.
Recently a complex of five proteins also found on the surface of the virus has been shown to induce strong neutralizing responses that protect against entry into many types of epithelial cells. In pregnant seronegative women it has been shown that rapid induction of those antibodies is correlated with protection against fetal damage. Accordingly, many candidate CMV vaccines contain this pentamer, with or without gB, and a molecule called pp65 that induces T cell responses.
Group B streptococci continue to cause deaths in newborns despite antibiotic prophylaxis. Unfortunately there are multiple serotypes of Group B streptococci based on their capsular polysaccharides. Conjugates of the most prevalent serotypes are being tested as candidate vaccines that could be given to pregnant women in an effort to passively protect the newborns (13).
Dengue is the most prevalent tropical virus infection and is complicated by the existence of four different dengue viruses. A single infection can cause febrile disease, but a subsequent infection with another serotype can cause serious hemorrhagic manifestations based on enhancement by heterotypic antibodies of entry into macrophages. A tetravalent vaccine containing the envelope structures of the four dengue viruses inserted into yellow fever virus particles has been shown to provide moderate protection to individuals previously exposed to dengue, but not previously unexposed children. Other candidate vaccines that also contain the internal antigens of dengue are being tested and may give better protection (21).
Everybody wants a vaccine against human immunodeficiency virus (HIV), but failures have been legion. However, several efforts are being pursued and we can permit ourselves a bit of optimism (24). The trial conducted in Thailand using a canary pox vector producing the HIV envelope protein followed by the envelope protein itself was a “game changer” in that there was some protective efficacy and it was due to non-neutralizing antibody-dependent cellular cytotoxic (ADCC) (2).
A new trial in Africa hopes to improve on the moderate efficacy. In addition, a regimen of adenovirus vectored HIV proteins followed by the envelope protein looks good in the clinic and will be subjected to an efficacy trial. Finally, structural biology has succeeded in making more immunogenic HIV surface protein. Thus, if a vaccine could produce neutralizing antibodies to the V3 loop of the virus, ADCC antibodies to the V2 loop, and antibodies blocking attachment of the virus to CD4, an HIV vaccine could result (26).
Tuberculosis remains a worldwide problem despite progress in medicine and economic advancement. The key difficulty is our lack of understanding about natural immunity, if that exists. A protective antigen in the usual sense has not been identified. The key seems to be to find a way to induce macrophages to kill the organism, rather than to harbor it (12).
The last of the big three is malaria. In this study it is clear that the circumsporozoite protein is key to preventing infection, as the infection begins by injection by the mosquito of the sporozoites. The difficulty is to prevent every single sporozoite from invading the liver, where it can replicate, change into merozoites, and then infect red blood cells. The new RTS/S vaccine does have moderate efficacy and will likely be useful, but new vaccines based on the sporozoites and the addition of antigens from later in the replication cycle of the malarial parasite will probably be necessary (18).
I will end with making two points about the future of vaccine production. First, it is evident that the five major western vaccine manufacturers (GSK, Johnson & Johnson, Merck, Pfizer, and Sanofi Pasteur) cannot supply the world with all the needed vaccines at a price that is affordable for low- and middle-income countries. The Serum Institute of India is now a major competitor for those markets and it is likely that Chinese, Brazilian, and other Indian manufacturers will be able to produce vaccines acceptable to licensing authorities. What is necessary is that they also participate in research and development of new vaccines.
Second, vaccines are needed on an urgent basis for emerging infections and infections in tropical areas that are not commercially appealing. A new organization, the Coalition for Epidemic Preparedness and Innovation (CEPI), has been formed with the financial backing of numerous countries (23). CEPI will fund academia, biotechnology organizations, and vaccine manufacturers to bring candidate vaccines against infections such as Lassa, MERS, and Nipah through development to stockpiles that could be used emergently in outbreaks or even prophylactically in susceptible populations (3).
Thus, as the 21st Century continues the future of vaccines is reasonably bright, as long as we are able to convince people to take advantage of the fruits of technologies that have literally changed the history of humanity for the better.
Footnotes
Author Disclosure Statement
S.A.P. is a consultant to many vaccine companies and biotechs, but none are mentioned in this article.