COVID-19: Pursuit of a universal coronavirus vaccine (4 January 2022)
The emergence of vaccine evasive SARS-CoV-2 variants, coupled with previous coronavirus outbreaks caused by severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and Middle East respiratory syndrome coronavirus (MERS-CoV), evince the ongoing threat posed by the coronaviruses (specifically the betacoronaviruses), as well as the potential benefit of a broadly effective coronavirus vaccine. Here, I briefly describe some of the challenges associated with constructing a universal coronavirus vaccine and comment on some of the recent developments made by several groups.
Because the currently available COVID vaccines work by inducing neutralizing antibody formation against the receptor binding domain (RBD) of the virus’s spike (S) glycoprotein (1), mutations that alter the RBD may diminish vaccine efficacy, necessitating boosters. Indeed, the Omicron variants currently in circulation (primarily 21K and 21L) have a large number of mutations in the gene that encodes the S protein, many of which are in the receptor binding domain. Some of these are believed to effect increased transmissibility, while others are associated with immune evasion (2). This is exampled by a study conducted by researchers at the Africa Health Research Institute who observed a 41-fold drop in the ability of Pfizer/BioNTech vaccine-induced antibodies to neutralize the Omicron variant compared with the wild type (i.e. original) virus (3). Consequently, Pfizer/BioNTech announced that “(t)he first line of defence (Sic), with two doses of vaccination, might be compromised and three doses of vaccination are required to restore protection” (4). However, recent data suggest that the protection conferred by even three doses of the Pfizer/BioNTech vaccine against symptomatic disease caused by Omicron drops from 70 percent to 45 percent within 10 weeks (5); and recently, the Israeli Health Ministry approved fourth doses for some high-risk individuals (i.e. age 60 years and older, those with immune compromising conditions, and healthcare workers) (6). That notwithstanding, the current tack seems to be constructing variant-specific boosters, and both Pfizer and Moderna have announced plans to develop boosters specific for Omicron and other variants of concern (7). This approach is similar to that taken for influenza vaccines, which are formulated to protect against those strains that are anticipated to be prevalent during each upcoming flu season. It is important to note, however, that this approach, while variably effective against influenza, may not be practical for COVID-19. In the northern hemisphere, seasonal influenza generally occurs in regular annual epidemics between October and May and in the temperate regions of the Southern Hemisphere, between April and September. This pattern provides vaccine manufacturers an opportunity to identify the prevalent strains in circulation and to prepare, mass produce, and distribute a corresponding vaccine in time for the beginning of flu season. In contrast, SARS-CoV-2 does not appear to be seasonal. Moreover, an error-prone replication process that is typical of RNA viruses, along with selective pressure (e.g. from vaccination), contribute to the ongoing emergence of SARS-CoV-2 variants (8). Included among these are the World Health Organization designated “variants of concern” (VOC) , so named because of their increased transmissibility, their increased virulence, or because of the decreased effectiveness of diagnostics, vaccines, or therapeutics. There are currently five VOC including Omicron, which emerged in November 2021 and quickly displaced Delta as the dominant variant (9). In light of this, the appeal of a broadly effective coronavirus vaccine becomes apparent, as such a “universal” vaccine would obviate the need to design, mass produce, and distribute a potentially endless number of variant-specific boosters at the drop of a hat. To this end, scientists at the National Institutes of Health have called for “an international collaborative effort to extensively sample coronaviruses” and for “the expeditious development of safe and broadly protective coronavirus vaccines” (10).
Ideally, any universal coronavirus vaccine would include a number of properties conferring both individual and collective immunity (11). Some examples of the former include robust immunity to multiple viral components and durable protection against a wide array of viruses (e.g. the betacoronaviruses) as well as their variants. Moreover, a vaccine should not produce paradoxical antibody-dependent enhancement with subsequent wild-type virus exposure (as is the case with dengue). Examples of necessary or desirable properties of collective immunity include a platform that is easily upgraded with new antigens, prevention of community transmission, and induction of durable herd immunity. Not surprisingly, there are challenges to creating such vaccines. Consider, for example, that more than two hundred different viruses are known to cause the common cold, and many of these (such as the rhinoviruses) consist in turn of myriad distinct species and clades (12). Another potential obstacle is the fact that the conserved (i.e. unchanging) portions of viruses which would be logical targets of universal vaccines may be internal to the virus rather than externalized on the surface (like the SARS-CoV-2 spike protein) and potentially less immunogenic. Moreover, antibodies produced against these components do not necessarily confer long lasting protective immunity. For example, antibodies induced by current influenza vaccines are associated with narrow and short-lived protection (13).
These challenges notwithstanding, a number of groups are researching a universal COVID vaccine. Among these is the Walter Reed Army Institute of Research or “WRAIR” (where I was once deputy commander). Recently, the WRAIR published results from tests in nonhuman primates of a novel vaccine consisting of ferritin (a naturally occurring spherical iron-carrying protein) conjugated with an array of SARS-CoV-2 spike proteins and co-formulated with a liposomal adjuvant called ALFQ (a substance that enhances the body’s immune response to an antigen) (14). In this study, Rhesus macaques were vaccinated with either 50 or 5 μg of the spike ferritin nanoparticle vaccine (SpFN) 4 weeks apart, or once, 4 weeks prior to a respiratory challenge with 1x10(6) 50% tissue culture infective dose of SARS-CoV-2. The WRAIR researchers then measured both humoral (i.e. antibody) and cellular immune responses in animals after each vaccination and after viral challenge. Among the vaccinated animals, the researchers observed that 1) SpFN vaccination elicited neutralizing antibody responses; 2) SpFN vaccination elicited spike protein-specific helper CD4 T cell responses; 3) SpFN vaccination reduced viral load in saliva and bronchoalveolar lavage fluid after respiratory SARS-CoV-2 challenge; and 4) SpFN vaccination provided protection from lung pathology after SARS-CoV-2 challenge. Additionally, SpFN elicited broadly neutralizing antibodies against four VOC, including Alpha, Beta, Gamma, and Delta (This study was completed before emergence of the Omicron variant and presumably, the group is testing or will test their vaccine against this VOC as well). Interestingly, because ferritin self-oligomerizes into a spherical particle with 24-facets, each of which can be conjugated with a spike protein, SpFN could be constructed to array up to 24 different spike proteins.
Encouraged by the results of their nonhuman primate trial, the WRAIR researchers subsequently conducted a phase 1 human clinical trial of their SpFN/ALFQ vaccine (15); and according to a 22 December 2021 WRAIR announcement, the study results will be made public once the analysis is complete and published in a peer-reviewed journal (16). Nonetheless, early reports are reportedly promising (17).
Several groups in addition to WRAIR are similarly investigating nanoparticles as a platform for coronavirus vaccines. One such effort is a large multinational collective spearheaded by the Institute for Protein Design at the University of Washington and comprised of academia and industry in Europe and the United States. Their vaccine candidate, a multivalent SARS-CoV-2 receptor-binding domain nanoparticle vaccine (SARS-CoV-2 RBD-NP), consists of a 120-subunit icosahedral protein resembling a viral capsid (the protein shell of a virus) studded with an array of (the receptor-binding domain of) spike proteins (18). In a proof or principle study, mice vaccinated with SARS-CoV-2 RBD-NP produced high titers of neutralizing antibodies and were protected against severe illness when challenged with virus (19). Furthermore, SARS-CoV-2 RBD-NP elicited robust neutralizing CD4 T cell responses in nonhuman primates and conferred protection against a respiratory challenge with SARS-CoV-2 (20). This vaccine candidate is currently being evaluated in two phase 1 and 2 clinical trials (21,22)
Not all universal COVID vaccine research being conducted is based on a nanoparticle platform conjugated with spike proteins. Another approach incorporates instead the SARS-CoV-2 nucleocapsid protein (N) into various vector platforms. The coronavirus nucleocapsid protein is a multifunctional structure within the capsid that encases the viral RNA and plays a role in transcription and viral assembly (23). The genes encoding coronavirus N proteins are generally conserved and stable, showing fewer mutations over time (24). Moreover, coronavirus N proteins are abundantly expressed during infection and are immunogenic (25). That notwithstanding, they do not appear to elicit protective antibodies to the same extent as do S proteins. However, at least one study suggests that N and S proteins might be synergistic in inducing protective antibody titers (26).
One particularly unconventional approach in the pursuit of a universal vaccine is being taken by Innovative Therapies, Inc. (ITI), an Israeli biopharmaceutical company founded in 2004. Rather than pursuing a traditional antigen-presenting vaccine designed to prime the immune system against subsequent challenge by SARS-CoV-2 and other coronaviruses, ITI researchers propose instead to use differentiated and expanded T helper type 1 (Th1) cells (AlloStim®). The proposed mechanism involves vaccination with a bioengineered living allogeneic cellular vaccine derived from healthy blood donors and currently in clinical use as an experimental cancer vaccine (27). According to the ITI researchers: “The vaccine is designed to create high titers of memory immune cells that are specific to the foreign antigens in the living cell vaccine. Upon encounter with any type of virus, these memory immune cells are activated and release cytokines including an immediate release of IFN-ϒ. This non-specific activation causes immune conditions similar to the conditions that occur in healthy younger patients that leads to rapid viral clearance and viral-specific memory immune response to clear infection and protect against recurrence.” The ITI researchers envision that this “allo-priming” mechanism will be most useful as an adjuvant for traditional vaccines, especially for those with immunosenescence (i.e. the elderly) (28). This can be thought of as an attempt to confer upon the elderly, who are at increased risk of severe disease from SARS-CoV-2 and other viruses, a level of immune protection typically associated with younger individuals. Phase 1 and 2 clinical trials testing the safety and efficacy of the AlloStim® cells are actively recruiting study participants and are scheduled for completion on 31 December 2022 (29).
The ongoing COVID-19 pandemic, now entering its third year and propagated by the emergence of increasingly transmissible and vaccine evasive SARS-CoV-2 variants, underscores the appeal of a broadly effective coronavirus vaccine. As is often the case, however, this may prove to be easier said than done. Despite their relative simplicity (i.e. when compared to prokaryotic and eukaryotic cells), viruses and the ways in which they interact with their hosts are amazingly unique and complex. Although an in-depth review of viruses is far beyond the scope of this post, consider that there are some viruses (e.g. measles, mumps, polio, smallpox/variola, and varicella) for which there are very protective vaccines, yet other viruses (e.g. hepatitis C and HIV) for which no effective vaccines are available despite decades of research. It remains to be seen when or even if an effective universal COVID vaccine will be realized. Our understanding of SARS-CoV-2 is incomplete and there are a number of yet unanswered questions, to include what the systemic and mucosal immune correlates of protection are and whether or not antibodies against the more conserved portions of the virus will be sufficiently protective. In the end, it may prove necessary to pursue the more modest goal of a vaccine that is effective against a particular genus (e.g. Betacoronavirus) or even subgenus (e.g. Sarbecovirus) of the Coronaviridae, rather than all coronaviruses. Nonetheless, as interminable as the pandemic seems, it is noteworthy that within just two years medical research has produced a number of reasonably albeit variably effective preventatives and therapeutics; and the progress being made in these areas, to include the pursuit of vaccines that are broadly effective and confer durable immunity, may justify cautious optimism.
As with my prior COVID-19-themed posts, my intention here is not to politicize, sensationalize, or trivialize the pandemic, but only to provide timely information and thoughtful commentary.
Until my next update — regards.
Michael Zapor, MD, PhD, CTropMed, FACP, FIDSA
(4 January 2022)
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