Introduction

In human history, it is an old insight that many transmissible (infectious) diseases or plagues induce a long-lasting immunity [1]. The first scientific description of such a plague was given by Thukydides in his history of the Peloponnesian War (431–404 B.C.). Early physicians tried to induce immunity by inoculating pathogenic material into a healthy individual. The classic example of those first immunisations is small pox (variola major). Usually, healed skin lesions from surviving patients were applied. The virulence of such materials was attenuated by drying or heating. However, the outcome of such a “variolation” was often hazardous. Many inoculated people fell ill and died. The big breakthrough was achieved, when at the end of the eighteenth century, the English physician Edward Jenner investigated and confirmed an old country saying: Cowpox transmitted to a human does not harm. It is restricted to small skin lesions and mediates immunity against small pox for some years. The rather safe “vaccination” was borne. Half a century later on, the microbial or viral aetiology of infectious diseases was discovered by L. Pasteur, R. Koch and others. Both founders of microbiology were engaged in vaccine development. L. Pasteur succeeded in developing a vaccine against rabies by the use of Jenner's technology which was advanced by him. R. Koch, who had discovered the mycobacterium as the infectious agent of tuberculosis, was the first who (in vain) tried to develop a therapeutic vaccination by preparing wall material out of the bacterium (tuberculin). Koch’s approach was not to prevent the mycobacterial infection, but to suppress its pathogenicity (tuberculosis). Therapeutic vaccination against tuberculosis is a current issue up to date, in particular after the emergence of multidrug-resistant TB cases [2]. Koch’s disciples Emil von Behring and Paul Ehrlich investigated the immune system and recognised that the prevention of infection is mediated by antibodies [3]. The antibodies are produced by special B lymphocytes triggered by T helper lymphocytes of the TH2 subgroup. Both are partially converted to long-living memory cells. Ilja I. Metschnikow, a contemporary of von Behring and Ehrlich, recognised the role of phagocytising and cytotoxic cells as initiators and effectors (killers) of the specific immune response, among them the macrophages and Tc cells. These cells play a crucial role for the recovery of many infectious and, in particular, viral diseases.

In the following decades up to date, an increasing number of vaccines were developed and successfully applied along to the rapid development of microbiology and virology. The huge technological progress helped to produce effective and safe vaccines by conventional technology (cultivation), by the use of molecular biology (DNA recombination), or by synthetic chemistry. Whole attenuated infectious agents or selected structural components of them are prepared. A recent alternative is the injection (transfection) of genomic material (DNA vaccines) [4–6]. Furthermore, as a consequence of the revolution in diagnostics, techniques are now available to monitor the vaccine on consistency and stability in terms of biologic and molecular biologic levels [7–9]. Modern immunology revealed that part of the complex immune system must be stimulated to get a long-lasting immune protection. Innate initial immune responses, localised inflammation and antigen uptake processes, are crucial whether all branches of the specific immunity (B and T cell responses) are activated or only the antibody production [4, 10]. To improve the efficacy of the initial innate immune response, adjuvants and special techniques of vaccine application have been developed and their hazards discussed [6, 11, 12].

Vaccination has proven to be one of the best weapons protecting the mankind against infectious diseases. However, the microbial empire fights back as is the usual way of evolution. Today, we know that eradication of infectious diseases equals Sisyphus' labour.

What can we achieve by vaccination? What are the realistic perspectives?

Successes and failures of vaccine developments

The World Health Organisation (WHO) has established eradication programmes for several infectious diseases. Small pox was eradicated, nearly two centuries after the advent of vaccination. Apart from common vaccination, important premises for this success were the antigenic stability of the human pox virus and the species restriction of poxviruses in the animal kingdom. The next candidate of eradication is poliomyelitis. Although wide parts of the world have been certified to be poliovirus free, the virus survived in some regions (Nigeria, Pakistan) and may threaten the globalised world, since vaccination activity has decreased [13, 14]. Like pox virus, also poliovirus is strictly human specific, but on the contrary, this infection reveals a very low manifestation index (poliomyelitis) which makes survey programmes much more elaborate. Furthermore, there are a lot of other similar enteroviruses circulating in mankind and revealing a considerable mutation rate [15, 16]. HAV, HBV, measles, mumps and rubella are human specific, too. Nevertheless, through worldwide and intensive vaccination campaigns, a definite eradication was not reached up to date. Nevertheless, vaccination programmes must not stop [17, 18], even if an escape mutant emerges, as e.g., reported for HBV [19]. However, antiviral therapy for chronic hepatitis B (CHB) has improved the outcome of patients. Due to the multiple selection pressures of different nucleos(t)ide analogue, drug-resistant HBV variants have emerged. Because of the arrangement of overlapping reading frames in HBV genome, these variants not only have clinical implications such as drug resistance, but also the potential to pose public health issues via vaccine escape [20]. Addition of the preS1 peptide in a highly immunogenic form to the current hepatitis B vaccine may improve protective immunity and reduces selection of escape mutations [21].

While most infections can be prevented by passive immunisation for the short term, this measure fails in HCV infections. The propensity for HCV to establish chronic infection, to re-infect previously exposed individuals, to transmit directly by cell–cell routes in vitro and to evolve neutralisation escape variants makes the development of a HCV vaccine a major challenge [22]. Correspondingly, no active vaccination is available against HCV despite promising approaches [23, 24].

The situation is much more complicated with infectious agents which do not only affect humans, but are spread in the animal kingdom, too. For these microbes or viruses, an eradication programme does not seem to make big sense, even if the infectious agent reveals antigenic stability and similarity in humans and animals. This is illustrated, e.g., by the spread of hepatitis E virus even in developed countries [25, 26].

Influenza A viruses have their main reservoir in (watery) birds. Up to date, >100 subtypes have been identified. A lot of them are sporadically transmitted to other birds, in particular to chickens, causing outbreaks of fowl pest. Where contacts of fowl and humans are close like in China and South-East Asia, direct transmission to humans happens usually causing severe respiratory disease, by which the public health services are alerted and instant measures are taken to prevent an epidemic [27, 28]. Concerning these cases, a lot of new research on influenza pathogenicity was done [29–32]. Pigs are considered the main vector of influenza A virus to mankind. This has been recently shown again by the worldwide epidemic of swine-origin influenza virus A/H1N1pdm [4, 33]. It has now replaced the conventional H1N1 strain, which had re-emerged 1978, as many seroprevalence studies show [34–37]. Based on recent research on avian flu [38], modern vaccines against the new human H1N1 strain could be rapidly created and applied [39–41]. Vaccination is the main weapon against influenza facing current development of neuraminidase-resistant virus strains [42]. However, influenza vaccines have a very modest effect in reducing influenza symptoms and working days lost in the general population [43]. To fight the spread of influenza in mankind is an old and permanently recurrent challenge caused by virus antigenic drifts and shifts which bypass the immune protection and require current vaccine adaptations. In this regard, vaccine strategies that generate antibodies with reactivity against an array of influenza viral strains could reduce the need for yearly influenza vaccination and increase our preparedness for potential pandemics [44]. The strategies of universal vaccines include the matrix 2 protein, the hemagglutinin HA2 stalk domain and T cell-based multivalent antigens [45]. In a similar way, also many other microbes and parasites escape human immune response, among them malaria, which is one of the biggest infectious problems of mankind in the world [46].

In elderly patients, in addition to influenza, pneumococcal vaccination is recommended. At present, two anti-pneumococcal vaccines are available for use in adults: the 23-valent pneumococcal polysaccharide vaccine (PPV23) and the 13-valent protein-polysaccharide conjugate vaccine (PCV13). The major advantage of the PPV23 is that it may provide protection against ten additional serotypes. However, the protein-polysaccharide conjugate PCV13 may be more effective because of its higher immunogenicity [47, 48].

Polysaccharide vaccines were initially introduced in the late 1960s for preventing meningococcal diseases, but their poor immunogenicity in infants and toddlers and hyporesponsiveness after repeated doses have led to the development and use of meningococcal conjugate vaccines, which overcome these limitations [49]. Recently, in Europe, a quadrivalent meningococcal vaccine comprising three immunogenic antigens (identified with use of reverse vaccinology) combined with bacterial outer-membrane vesicles has been licensed. The vaccine has the potential to reduce mortality and morbidity associated with serogroup B meningococci infections, but uncertainty remains about the breadth of protection the vaccine might induce against the diverse serogroup B meningococci strains that cause disease [50].

Furthermore, a special mode or entry site of microbes may favour super-infections. The epidemiologic differences between HSV and VZV, two closely related human herpes viruses, illustrate this aspect. VZV is transmitted by air droplets, HSV by intimate or sexual contact. VZV-primary disease (varicella) induces immunity against varicella, although the virus persists lifelong in the paravertebral ganglia of sensory neurons. The immunity against VZV reinfection depends on serum antibodies. By application of hyperimmunoglobulin, passive immunisation is possible. The infection may be reactivated, when the number of specific T lymphocytes decreases, even if the individual reveals many specific antibodies. Stimulation of cell-mediated immunity by the injection of attenuated VZV vaccine may protect against herpes zoster, a reactivation of persistent VZV infection in older or immunocompromised people. However, these vaccinations do not reliably work in each vaccinee [5, 40, 51].

Like VZV, also HSV infection stimulates antibody production and T cell formation. However, passive immunisation with Ig preparations is not successful. HSV persists lifelong in the same (cerebral and sacral) ganglia as VZV. In opposite to VZV, cell-mediated immunity provides only partial protection against HSV. It prevents chronic active infection as seen in treated HIV patients after immune reconstitution. However, recurrences of latent infection are frequent, also in immunocompetent hosts. Furthermore, super-infection by the heterologous HSV serotype is well known, although in vitro a strong cross-neutralisation between HSV-1 and HSV-2 can be determined because of common epitopes on the viral envelope. Moreover, intra-typic HSV reinfections have been observed in immunocompromised people [4, 52]. An HSV vaccination, in particular to prevent herpes genitalis, is still missing [53].

Apart from recurrences, reinfections have also been recorded with HCMV. It is assumed that pre-existing neutralising antibodies may attenuate the pathogenic consequences of cytomegalic inclusion disease as seen in immunosuppressed patients receiving hyperimmunoglobulin [54, 55] and in the statistically different outcome of newborns from HCMV-affected pregnancies of seropositive and seronegative women. Since about 50 % of the young adults are seronegative in the developed countries, much labour is done to develop a vaccine [56, 57].

HIV is the infectious agent which originates from a zoonotic reservoir. It reveals the biggest antigen drift and a special mode of infection to bypass immunity. The natural way of horizontal infection is blood microtransfusion in small lesions during sexual intercourse. Furthermore, vertical infection happens as materno-foetal transfusion during the labours at the end of pregnancy. Apart from free virus particles, intracellular viruses and proviral genomes are transmitted with lymphocytes. A lot of approaches are done to trace the way of infection and epidemiologic spread of HIV [58–60] along with the current introduction of diagnostic test systems [61–63]. Currently, more and more HIV-1 subtypes and intra-subtype variants of HIV are discovered hampering the development of antivirals and vaccines. HIV heavily damages the immune system by cytolytic infection of Th lymphocytes. In opposite to measles or infectious mononucleosis, the immune system does not recover from this challenge, but proviral persistency plus antigen drift of ongoing HIV reactivations prevent a sustainable protection [61, 64, 65]. Finally, the immune system is exhausted and breaks down. Albeit biggest labour no efficacious vaccination could be produced up to date [5]. However, pathogenic research is in progress looking for measures to enhance the cellular-mediated immune response [66–71].

Coming back to tuberculosis: Mycobacterium tuberculosis is antigenetically stable. However, it resists the attack of the immediate innate immune response. The bacterium is phagocytised, but not killed due to a special wall structure. The mycobacterial pathogenicity is restricted by the formation of granulomata consisting of macrophages. The mechanisms of inflammation and immune responses are complex [72]. Recurrence of tuberculosis is favoured, when the organism is weakened by other factors (malnutrition, metabolic disorders, etc.). Huge labours have been done, to develop a reliable preventive or therapeutic vaccination against tuberculosis. However, conventional approaches have been failed up to date. So, no ways have to be taken [73] hoping that “combined efforts in immunology and vaccinology will lead to effective vaccines against HIV, tuberculosis and malaria” [74].

Perspectives

Is it possible to create a vaccine against an infectious disease which does not naturally leave immunity? The answer is no—with some remarkable exceptions: diphtheria and tetanus do not leave a lifelong, but only a timely restricted immunity. Disease is caused by toxins released from Corynebacteria diphtheria, respectively, Clostridium tetani. After recovery, specific antibodies protect against these toxins. However, if toxin production has ceased, antibody formation declines [75]. Reinfection happens causing a second disease. Thus, revaccination (or antibody determination) is necessary in case of permanent or occasional exposition to the infectious agents, in particular for immunocompromised individuals [76].

Cervical carcinoma is caused by special HPV types 16, 18 and others in combination with other factors [77, 78]. HPV infection does not leave immunity. Innate immune response and specific antibody production is not sufficiently and sustainably stimulated by natural infection [79]. By the use of virus-like particles, a highly immunogenic immunisation can be established resulting in the production of neutralising antibodies which protect against infection [80, 81]. This success is very remarkable, since most vaccination approaches failed in sexually transmitted and localised diseases.

Recently, in an experimental setting, skin tumours could be prevented in HPV-8 transgenic mice by HPV8-E6 DNA vaccination. Protection was not provided by antibodies, but by TC lymphocytes [82].

Adoptive transfer of specific lymphocytes to immunosuppressed or immunocompromised patients has proven to provide protection against diseases caused by several viruses and fungi for some weeks, in particular in immunocompromised patients [83].

Conclusions

From these examples, two rules may be deduced for future vaccine developments: They are promising, if

  1. 1.

    The natural infectious disease leaves immunity or

  2. 2.

    Passive immunisation is successful (transfer of antibodies, adoptive transfer of specific lymphocytes).