key: cord-1039716-f38pftlm authors: Tannock, Gregory A.; Kim, Hyunsuh; Xue, Lumin title: Why are vaccines against many human viral diseases still unavailable; an historic perspective? date: 2019-10-03 journal: J Med Virol DOI: 10.1002/jmv.25593 sha: 3970ee2ea0ca0f8a7b38a8cdc6f6da5360a25b9b doc_id: 1039716 cord_uid: f38pftlm The number of new and improved human viral vaccines licensed in recent years contrasts sharply with what could be termed the golden era (1955‐1990) when vaccines against polio‐, measles, mumps, rubella, and hepatitis B viruses first became available. Here, we attempt to explain why vaccines, mainly against viruses other than human immunodeficiency virus and hepatitis C virus, are still unavailable. They include human herpesviruses other than varicella‐zoster virus, respiratory syncytial and most other respiratory, enteric and arthropod‐borne viruses. Improved oral poliovirus vaccines are also urgently required. Their unavailability is attributable to regulatory/economic factors and the properties of individual viruses, but also to an absence of relevant animal models and ethical problems for the conduct of clinical of trials in pediatric and other critical populations. All are portents of likely difficulties for the licensing of effective vaccines against emerging pathogens, such as avian influenza, Ebola, and Zika viruses. were licensed over the same period. 4 The development of HPV vaccines, in particular, provide a powerful example of the potential for recombinant DNA technologies in vaccine development. This is not to deny the critical molecular role of reverse genetics in the development and manufacture of some human vaccines and others under development. [5] [6] [7] Reasons, why vaccines against human immunodeficiency viruses (HIV) are unavailable, are complex and have been comprehensively dealt with elsewhere. 8 However, despite monumental efforts over 30 years, vaccines for the prevention and/or prophylaxis of infection by HIV still appear to be some years away. It now appears that much early misplaced optimism can be attributed to the fruits of the premolecular era and should have been tempered by a realization that, for reasons still largely unknown, immune responses to animal lentivirus infections very rarely result in long-term reductions in viral load and accompanying pathogenesis. 9 The same is true of several members of the genera Hepacivirus and Pestivirus of the family Flaviviridae, as represented by HCV and several veterinary viruses that produce chronic infections. The absence of much-needed vaccines against herpes simplex virus types -1 and -2 (HSV-1, -2), respiratory syncytial viruses (RSV), most other respiratory and arthropod-borne viruses (except Japanese encephalitis and, until very recently, dengue viruses) and genetically stable liveattenuated oral poliovirus vaccines (OPVs) is attributable to the properties of individual viruses and to the deficiencies of currently used animal models of human pathogenesis, notably mice. 10 It is also partly due to a continuing and inevitable disconnect with veterinary virology where the relevance of animal models is rarely an issue. These factors, together with the difficulties and prohibitive costs of conducting Phase III clinical trials on vaccines against newly emergent pathogens, 11 The decreasing numbers of commercial manufacturers have been driven, in part, by the need to achieve economies of scale in the manufacture and by an increase in testing requirements before vaccine release that have been underpinned by codes of good manufacturing, laboratory, and clinical practice (GMP, GLP, and GCP). These codes in large measure have resulted from the willingness of US courts in earlier years to sanction significant claims against manufacturers, some for negligence but others now attributable to gaps in our knowledge of molecular aspects of viral replication and immunology, unknown at the time of the initial registration. The role of government in underwriting liability for manufacturers in national immunization programs has markedly Accreditation of both types of cell culture signified a major shift in thinking by regulators as to their oncogenic potential. 12 Until then, continuous cell lines had been used for the preparation of veterinary viral vaccines and shown to be safe and efficacious for animals but disallowed for use in the preparation of human vaccines. Without these changes, it is doubtful whether many highly successful vaccines against poliovirus, measles, mumps, and rubella would still be available today. This is especially true for OPVs prepared from primary monkey kidney alarmingly in the case of measles, vaccination followed by the natural challenge is associated with immunopathologic disease. 16 The development of experimental vaccines for neonates also presents unique immunological and ethical difficulties. Respiratory syncytial virus (RSV) infections are the cause of over 30% mortality in infants less than 1 year of age. 16 Early attempts to use formalin-inactivated virus in an experimental vaccine not only failed to protect against infection but sensitized the recipients to severe adverse (Arthus) type III hypersensitivity reactions that resulted from subsequent natural challenge. 17 Indeed Passive immune therapy (PIT) has been a historically successful approach to the prevention or treatment of some intoxications or viral infections. 18 The use of immune gamma globulins has been largely abandoned because of the risk of anaphylaxis or blood-borne virus transmission and currently, their use is not feasible for populationbased coverage. However, the emergence of monoclonal antibody (mAb) therapy in inflammation and cancer has raised the possibility that PIT may be useful in the acute management of viral infections as alternatives to traditional vaccines for use in infants, such as RSV whose development has been problematic. The mAb, Palivizumab, has been licensed for clinical use in the prevention of RSV infection. Combinations of up to three therapeutic mAbs have also been considered for development as a possible PIT in Ebola virus infections. 19, 20 A related development in the use of postexposure prophylaxis, involves the use of combination passive and active immunization which is widely used for the treatment of verified rabies infections. 21 It has become apparent that anticancer antibodies act, at least in part, by harnessing effector responses of the innate immune system (antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell-mediated phagocytosis (ADCP) or complement activation. 21 Most interestingly, they can also induce active immunity to tumor cells. 22 The induction of adaptive immunity associated with mAb therapy involves cooperation between innate and adaptive immune systems and is probably related to the long-recognized and potent capacity of antibody-antigen (immune) complexes to alter immune responses. This includes the induction of immunological memory, which has been recognized for over three decades. [22] [23] [24] Whether such vaccinal effects will result from the use of anti-RSV or other antiviral mAbs remains to be seen but it is clear that passive TANNOCK ET AL. antibody therapy can induce active and durable adaptive immune responses. Thus, as a general consideration, it does not require a great stretch of the imagination to believe that passive antibody therapy of infectious disease, either as a monotherapy in established infections or in combination with the use of conventional inactivated vaccines or other vaccine candidates, may result in sterilizing responses to otherwise difficult infectious agents. Indeed, experimental evidence for this is beginning to emerge, albeit slowly. 25, 26 Perhaps a radical rethink on how to approach immune responses/ immunity may offer transformational change. Continuing improvements have been made to measles, mumps, and • Oral rotavirus vaccines. • Intranasal live attenuated influenza vaccines (LAIVs). • Subcutaneous varicella-zoster virus (VZV) vaccines. • An oral adenovirus vaccine, containing type 4 and 7 viruses and licensed for limited institutional use, such as the military, but not discussed here. Greater recognition of influenza as a preventable disease of children has led to recommendations in some countries for annual vaccination of infants and children. Data largely from animal studies has consistently indicated that not only are live experimental vaccines most effective but that direct administration via the respiratory tract yields superior protection than that afforded by parenterally-administered inactivated vaccines. 32 A previous attempt to develop a novel intranasal inactivated vaccine using a mucoadhesive adjuvant was abandoned following the demonstrated but unknown association between vaccine administration and the symptoms of Bell's palsy. 33 However, live attenuated coldadapted (ca) reassortant vaccines have been in use in the United States and Russian Federation for over a decade. 34 The initial 2002 approval in the United States restricted their use to 5 to 49-year-old recipients. Following receipt of further trial data, the age range for US vaccines was extended to 2 to 49 years in 2006. Live intranasally (i.n.) administered vaccines have been a significant component of US immunization programs since then. However, because of poor efficacy against more recent H1N1 swine pandemic viruses, use of the vaccine was temporarily suspended in the United States. 35 In vivo tests of immunogenicity that measure differences between individual vaccine components are no longer required for influenza vaccines. In the case of inactivated vaccines, potency is merely estimated by an in vitro antigen-binding assay to determine hemagglutinin (HA) antigen concentration. 36 Although not required for the licensing of the individual components of live vaccines, effectiveness can be measured in a mouse model according to the intranasal vaccination dose required to clear a standard challenge of the wild-type (wt) parental virus used to prepare 6:2 reassortants from the same attenuated donor strain and the vaccinating dose can be adjusted accordingly. In the case of earlier H1N1 reassortants,~100× the infectious dose was required to achieve clearance from the lungs 3 days after challenge, in comparison with the dose required for early H3N2 reassortants. 37 Other issues that do arise concern the relevance of HAI antibody as a measure of the effectiveness of live influenza vaccines. Virus-specific secretary antibody responses, as determined by ELISPOT assays in the respiratory tract of mice, clearly indicate the superiority of live vaccines but, for ethical reasons, cannot be performed in humans. However, overall, despite recent experiences, ca live reassortant vaccines appear more effective in children than conventional trivalent inactivated vaccines, whose role in the prevention of influenza has been the subject of contention for many years. 38 • Use of inappropriate viruses to obtain predictive data in animal models (eg, mouse-adapted influenza and respiratory syncytial viruses; other viruses of uncertain passage history). • Lack of recognition that, despite legitimate concerns as to the possibility of reversion to virulence, immunity to most human viral diseases is best achieved by live attenuated viruses (eg, herpes and TANNOCK ET AL. | 133 enteric viruses; RSV and respiratory viruses, including influenza; other viruses whose pathogenesis is complex and dependent on amplification in more than one target organ, such as measles and yellow fever viruses. • The possibility that some live herpesvirus vaccine viruses will undergo latency during replication, followed by recrudescence and subsequent infection by pathogenic viral progeny (eg, HSV-1 and -2). However, for live veterinary herpesvirus vaccines, reported problems from recrudescence have been few, the best example being the herpesvirus of turkeys (HVT) that has been used for over 40 years for control of Marek's disease virus (MDV), an oncogenic avian herpesvirus and a cause of great economic loss in intensively raised chickens. 47 Until the mid-1990s, HVT was the first and only example of an effective vaccine in either animals or humans that could be used for the prevention of neoplastic viral disease. The genome of HVT has 70% to 80% nucleotide homology with pathogenic MDVs but is completely innocuous for chickens. The effectiveness of live human VSV and MDV and other veterinary vaccines suggests that it may be worth revisiting the development of live vaccines using more readily cultivable human herpesviruses. • The inability of many human viruses to either grow in cell cultures • The variable stalk region of the HA and the identification of broadly neutralizing antibodies from different regions of the stalk, using so-called headless proteins as antigens. [59] [60] [61] [62] [63] [64] [65] [66] Other groups have attempted to design vaccines containing small conserved regions of the stalk. However, it is not known why antibodies are not normally made to the stalk as a consequence of infections by influenza A viruses. Good cross-protection across H3N2 sub-types was shown from earlier studies in mice but cross-protection against H1N1 viruses was less impressive. • Chimeric viruses prepared from high-yielding vectors with internal group-specific antigens. Vectors include vesicular stomatitis virus, adenoviruses, or poxviruses. [67] [68] [69] At issue is whether the long-term administration of common vector antigens inhibits specific responses to the inserted surface antigens of new pandemic viruses. • Pseudotypes that do not produce infectious progeny, but induce satisfactory short-term protective responses in mice after i.n. administration, including antibody to both HA and NA surface antigens, CTL and resistance to challenge. 70,71 Importantly, they have been shown to be effective in heterotypic challenge experiments in ferrets whose pathogenesis is similar to that of humans. 72 Such an approach could provide short-term protection in the initial stages of a pandemic. Live attenuated vaccines are usually superior at inducing immunity to viruses involving multiple target organs (eg, yellow fever, measles, mumps, and rubella viruses) than nonreplicating inactivated vaccines. Despite the shortcomings of some older vaccines, we should be extremely thankful for what has been achieved. We are fortunate that control of critical diseases, such as poliomyelitis and measles, was accomplished at times much less litigious than the present and, perhaps counter-intuitively, when much less was known of molecular aspects of viral replication and pathogenesis than is known today. It also occurred in the absence of the present day anti-vaccination lobby that ignores the lessons of the past and especially the concept of vaccine-induced herd immunity. However, success continues to be achieved against a background of overwhelming public acceptance of the need to control the pediatric disease by vaccination. What hope for recombinant vaccines? 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Efficacy and effectiveness of an rVSV-vectored vaccine in preventing Ebola virus disease: final results from the Guinea ring vaccination, open-label, cluster-randomised trial (Ebola Ça Suffit!) World Health Organization. Dengue vaccine WHO position Technical advisory group on dengue vaccines in late stage development Protective efficacy of multiple vaccine platforms against Zika virus challenge in rhesus monkeys Modified mRNA vaccines protect against Zika virus infection Zika virus infection complicated by Guillain-Barré syndrome-case report, French Polynesia Results of a study of the reactogenic and immunogenic properties of live antipoliomyelitis vaccine The authors declare that there are no conflict of interests. All authors contributed extensively to the work of writing and editing this manuscript. Gregory A. Tannock http://orcid.org/0000-0001-9629-1460