Huge death count this autumn from ADE and cytokine storms?
These SARS-CoV vaccines all induced antibody and protection against infection with SARS-CoV. However, challenge of mice given any of the vaccines led to occurrence of Th2-type immunopathology suggesting hypersensitivity to SARS-CoV components was induced. Caution in proceeding to application of a SARS-CoV vaccine in humans is indicated.
They’re coming for the kids now.
The emergence of the disease SARS and the rapid identification of its severity and high risk for death prompted a rapid mobilization for control at the major sites of occurrence and at the international level. Part of this response was for development of vaccines for potential use in control, a potential facilitated by the rapid identification of the causative agent, a new coronavirus –. Applying the principles of infection control brought the epidemic under control but a concern for reemergence naturally or a deliberate release supported continuation of a vaccine development effort so as to have the knowledge and capability necessary for preparing and using an effective vaccine should a need arise. For this purpose, the National Institute of Allergy and Infectious Diseases supported preparation of vaccines for evaluation for potential use in humans. This effort was hampered by the occurrence in the initial preclinical trial of an immunopathogenic-type lung disease among ferrets and Cynomolgus monkeys given a whole virus vaccine adjuvanted with alum and challenged with infectious SARS-CoV . That lung disease exhibited the characteristics of a Th2-type immunopathology with eosinophils in the lung sections suggesting hypersensitivity that was reminiscent of the descriptions of the Th2-type immunopathologic reaction in young children given an inactivated RSV vaccine and subsequently infected with naturally-occurring RSV –. Most of these children experienced severe disease with infection that led to a high frequency of hospitalizations; two children died from the infection , , .
The conclusion from that experience was clear; RSV lung disease was enhanced by the prior vaccination. Subsequent studies in animal models that are thought to mimic the human experience indicate RSV inactivated vaccine induces an increased CD4+ T lymphocyte response, primarily of Th2 cells and the occurrence of immune complex depositions in lung tissues , , . This type of tissue response is associated with an increase in type 2 cytokines including IL4, IL5, and IL13 and an influx of eosinophils into the infected lung; , , , . Histologic sections of tissues exhibiting this type of response have a notable eosinophilic component in the cellular infiltrates. Recent studies indicate that the Th2-type immune response has both innate and adaptive immune response components , .
In addition to the RSV experience, concern for an inappropriate response among persons vaccinated with a SARS-CoV vaccine emanated from experiences with coronavirus infections and disease in animals that included enhanced disease among infected animals vaccinated earlier with a coronavirus vaccine . Feline infectious peritonitis coronavirus (FIPV) is a well-known example of antibody-mediated enhanced uptake of virus in macrophages that disseminate and increase virus quantities that lead to enhanced disease , . Antigen-antibody complex formation with complement activation can also occur in that infection and some other coronavirus infections in animals. Thus, concern for safety of administering SARS-CoV vaccines to humans became an early concern in vaccine development.
As a site proposed for testing vaccines in humans, we requested and were given approval for evaluating different vaccine candidates for safety and effectiveness. Two whole coronavirus vaccines, one rDNA-expressed S protein vaccine and a VLP vaccine prepared by us were evaluated in a Balb/c mouse model, initially described by others, of SARS-CoV , . The concern for an occurrence of lung immunopathology on challenge of mice vaccinated with an inactivated virus vaccine, as reported by Haagmans, et al. for ferrets and nonhuman primates, was seen by us after challenge of mice vaccinated with a SARS VLP vaccine . This finding was duplicated in an experiment reported here and was also seen in mice vaccinated with a range of dosages of a double-inactivated whole virus vaccine (DIV) and an rDNA S protein vaccine (SV) although the immunopathologic reaction appeared reduced among animals given the S protein vaccine when compared to those given the whole virus vaccine. In later experiments, these findings were confirmed and the vaccine utilized by Haagmans, et al. was also shown to induce the immunopathology in mice. Thus, all four vaccines evaluated induced the immunopathology; however, all four also induced neutralizing antibody and protection against infection when compared to control challenged animals.
In these various experiments alum was used as an adjuvant and this adjuvant is known to promote a Th2 type bias to immune responses . However, the immunopathology seen in vaccinated–challenged animals also occurred in animals given vaccine without alum. In an effort to determine whether an adjuvant that induced a bias for a Th1-type response would protect and prevent the immunopathology, we initiated an experiment where the DI PBS suspended vaccine was adjuvanted with Freund’s complete adjuvant, a Th1-type adjuvant. However, this experiment was aborted by the September, 2008, Hurricane Ike induced flood of Galveston, Texas. An experiment with a SARS-CoV whole virus vaccine with and without GlaxoSmithKline (GSK) adjuvant ASO1 in hamsters has been reported . This adjuvant is thought to induce Th1-type immune responses . The authors indicate no lung immunopathology was seen among animals after challenge, including the group given vaccine without adjuvant; however, whether the hamster model could develop a Th2-type immunopathology is uncertain. Finally, a number of other studies of vaccines in animal model systems have been reported but presence or absence of immunopathology after challenge was not reported.
A summary of the SARS-CoV vaccine evaluations in animal models (including the current report) that indicated an evaluation for immunopathology after challenge is presented in Table 2. As noted all vaccines containing S protein induced protection against infection while the studies with VEE and vaccinia vector containing the N protein gene only did not. Also shown is that a Th2-type immunopathology was seen after challenge of all vaccinated animals when evaluation for immunopathology was reported except the study in hamsters with a GSK whole virus vaccine. Thus, inactivated whole virus vaccines whether inactivated with formalin or beta propiolactone and whether given with our without alum adjuvant exhibited a Th2-type immunopathologic in lungs after challenge. As indicated, two reports attributed the immunopathology to presence of the N protein in the vaccine; however, we found the same immunopathologic reaction in animals given S protein vaccine only, although it appeared to be of lesser intensity. Thus, a Th2-type immunopathologic reaction on challenge of vaccinated animals has occurred in three of four animal models (not in hamsters) including two different inbred mouse strains with four different types of SARS-CoV vaccines with and without alum adjuvant. An inactivated vaccine preparation that does not induce this result in mice, ferrets and nonhuman primates has not been reported.
This combined experience provides concern for trials with SARS-CoV vaccines in humans. Clinical trials with SARS coronavirus vaccines have been conducted and reported to induce antibody responses and to be “safe” , . However, the evidence for safety is for a short period of observation. The concern arising from the present report is for an immunopathologic reaction occurring among vaccinated individuals on exposure to infectious SARS-CoV, the basis for developing a vaccine for SARS. Additional safety concerns relate to effectiveness and safety against antigenic variants of SARS-CoV and for safety of vaccinated persons exposed to other coronaviruses, particularly those of the type 2 group. Our study with a VLP SARS vaccine contained the N protein of mouse hepatitis virus and Bolles, et al., reported the immunopathology in mice occurs for heterologous Gp2b CoV vaccines after challenge . This concern emanates from the proposal that the N protein may be the dominant antigen provoking the immunopathologic reaction.