Cautious suggestions on a way out of a mismanaged Covid-19 pandemic

I will primarily elaborate on immunization strategies that may enable protection against new pandemics of highly mutable viruses while avoiding breeding of more infectious or even vaccine-resistant variants. At this stage of the Covid-19 pandemic, the single most important objective should be to make early multidrug treatment of Covid-19 broadly available. From what follows below, one will appreciate that immunization and early treatment are not mutually exclusive but could even nicely synergize.

Immunization during a pandemic of Sars-CoV-2 variants comes with a major challenge. As the host population is continuously under attack from the virus, it is critical to arm the immune system rapidly in ways that enable efficient neutralization of free-circulating virus or killing of virus-infected host cells. Rapid deployment of highly efficient immune defense mechanisms upon viral exposure would avoid productive infection or even enable abrogation thereof. This would not only benefit individual health but also public health in that it would protect non-immunized subjects from infectious contact exposure (a phenomenon called ‘herd immunity’) and prevent more infectious immune escape variants from adapting to suboptimal immune conditions and dominating the original wild type strain.

Although wild type Sars-CoV-2 (i.e., Wuhan-Hu strain) is rapidly neutralized by vaccine-induced spike (S)-specific antibodies (Abs) upon post-vaccination exposure, the virus can evolve to become more infectious and reproduce more efficiently when repeatedly exposed to suboptimal S-directed immune pressure. Mass vaccination campaigns conducted in the heat of a pandemic of a highly mutable virus generate plenty of opportunity for the virus to become exposed to suboptimal S-directed immune pressure when infecting vaccinees. The likelihood for such pressure to occur in any given vaccinee rises with increasing vaccine coverage rates. The lower the rate of Covid-19 disease and the higher the vaccination rate in younger and younger age groups, the more the contribution of enhanced viral infectiousness to increasing the infectious pressure in the population will outweigh the contribution of diminished disease to reduce this pressure. This is to say that mass vaccination will eventually cause a resurgence of infectious pressure and increase the likelihood for more infectious variants to i) break through the natural Ab-based immune defense of previously asymptomatically infected subjects and to ii) further evolve towards even more infectious or anti-S Ab-resistant variants. In other words, mass vaccination on a background of low morbidity rates and involving enrolment of younger and younger age groups will only expedite the evolution of dominant, more infectious variants towards full vaccine-resistance.

On the other hand, cytolytic T cell (CTL)-mediated immunity is thought to be critical to eliminate virus-infected cells at a later stage of infection and enable patients to recover from clinical Covid-19 illness. As the antigenic determinants (epitopes) targeted by these antigen (Ag)-specific CTLs are highly conserved among Sars-CoV-2 variants (and sometimes even across other coronaviruses), and as CTLs from subjects with a distinct genetic MHC class I background will target different epitopes, problematic viral immune escape from CTL-mediated immune responses is unlikely to occur. This already explains why the chances for recovering from acute Covid-19 disease are not dependent on the genetic MHC class I background of the host. Thanks to their cytolytic capacity, primed Ag-specific CTLs can readily eliminate Sars-CoV-2-infected cells and, for that matter, abrogate infection and protect infected subjects from (severe) disease.

However, because T cells are MHC class I-restricted, designing T cell-based vaccines that are capable of controlling viral infection across a genetically diversified MHC class I background has remained one of the biggest challenges in modern vaccinology. This is to say that, thus far, no T cell-based vaccine candidate has succeeded in inducing functional memory T cells that can effectively be recalled to universally (i.e., regardless of the immunogenetic background of the host) kill virus-infected target cells. However, vaccines that are capable of inducing such cytotoxic, ‘sterilizing’ immunity in an outbred population would be highly desirable as their efficacy would not be influenced by pre-existing Abs and could even benefit patients who have already contracted Covid-19 disease. Under an even more preferable scenario, vaccines to be used during a pandemic of a highly mutable virus would induce an immune response that upon recall (i.e., upon exposure to the pathogen) could kill virus-infected cells at a very early stage of infection, i.e., before mature virions are produced. Because such a type of vaccine would prevent productive infection, it would also prevent transmission and hence, contribute to establishing herd immunity.

In the absence of efficient, T cell-based vaccines, live virus could serve as an efficient inducer of both, Ag-specific memory B and T cells. Live virus efficiently primes the immune system and provides for a durable and more diversified immune response. This would already explain why recall of memory B cells as a result of re-exposure of previously live virus-primed subjects generates Ag-specific Abs that are capable of neutralizing a diversified range of more infectious variants (1-5). It is, indeed, increasingly acknowledged that there is no need for individuals who recovered from acute Covid-19 disease to receive a Covid-19 vaccine as their immune system got primed well enough to protect them from (severe) Covid-19 disease upon potential re-infection. This only underscores, once again, the importance of early Covid-19 treatment as proposed by Dr. Peter McCullough and others (6). Early treatment is not only preventing hospitalizations and saving lives but also speeding up recovery from disease, thereby enabling patients to more rapidly mount a full-fledged, long-lived immune response. The latter will not only protect themselves from severe, or sometimes even mild, Covid-19 disease upon re-exposure to the virus, or any of its variants, but also readily contribute to building herd immunity in the population. Early treatment is reminiscent of an immunization strategy called ‘infection and treatment’ (7). The latter refers to the induction of protective immunity by truncating the course of an infection with drug treatment. This strategy is particularly useful in case the pathogen is prone to escape specific immune responses and/ or endowed with vulnerable Ags that are, however, highly variable. Infection and treatment is thought to offer great potential for straintranscending protection (7). Although this strategy has primarily been described for immunization against parasitic diseases (e.g., malaria and schistosomiasis), it is reasonable to assume that it could be equally effective against highly mutable viruses that are prone to escape suboptimal selective immune pressure exerted on viral infectiousness by the host immune system. It is reasonable to postulate that In the course of a natural CoV pandemic, suboptimal selective immune pressure may occur in previously asymptomatically infected subjects when they become re-infected at a point in time where the concentration of their low affinity, S-specific Abs does no longer suffice to cause suppression of their natural, CoV-nonspecific Abs. When the decline in infectious pressure subsequent to a previous wave of Covid-19 disease is followed by stringent and broadly implemented infection prevention measures, suboptimal selective (i.e., S-directed) immune pressure can become more generalized across the host population. ‘More infectious’ immune escape variants will now be able to adapt to the immune pressure. As a result, these variants will now reproduce more efficiently than the original wild strain virus and become the dominant circulating virus. Another situation that is likely to broadly generate suboptimal immune pressure on viral infectiousness occurs when vaccines targeting viral infection-mediating Ags (i.e. mostly viral surface Ags such as S protein from Sars-Cov-2) are used in mass vaccination campaigns conducted during a pandemic. Mass vaccination campaigns conducted during a pandemic will typically increase the likelihood for vaccinees to come under infectious attack while being in the process of mounting vaccinal Abs. When this happens, the immature anti-S Ab response will exert suboptimal selective immune pressure on viral infectiousness as early Abs bind with low affinity and/or in low concentration to viral surface-expressed S protein.

Along the same line of reasoning, it would also be conceivable to immunize CoV-seronegative subjects with a live (i.e., replication-competent) attenuated, heterotypic CoV (e.g., an attenuated endemic common cold CoV) in order to induce cross-protective cytotoxic T cells (CTLs). Such a live attenuated vaccine would induce S-specific Abs that are not protective against Covid-19 infection and, therefore, not subject to viral immune escape and not promote enhanced viral infectiousness. However, recall of Ag-specific memory CTLs would lead to clonal expansion of these cells and thereby produce large numbers of Ag-specific, MHC class I-restricted effector T cells. By destroying virus-infected target cells, cytotoxic effector T cells would abrogate the infection and hence, prevent progression to Covid-19 disease. Live attenuated vaccines have been particularly useful for large scale immunization campaigns targeted at eradicating viruses such as smallpox and poliomyelitis virus (although the latter has not yet been fully eradicated). However, only S-seronegative subjects would be eligible for parenteral immunization with live attenuated CoV as heterotypic anti-S Abs can still bind Sars-CoV-2 and could, therefore, prevent vaccine take or put the vaccinee at risk of Ab-dependent enhancement (ADE) of disease. There is also always a risk that a live attenuated vaccine causes disease in immunosuppressed subjects. This issue could, however, easily be solved by monitoring vaccinees for clinical symptoms after immunization and treating them with antivirals, if needed.

Finally, there is yet another option for achieving fast, transmission-blocking immunity without promoting propagation of selective immune escape variants. As this approach is not based on targeting adaptive cytolytic T cells but innate NK cells, there would be no need for host cells to first become infected with live virus to efficiently prime a protective immune response. The concept is no longer fully theoretical but more work need to be done to advance it into the clinic (8). Alike potential induction of Ag-specific CTLs by Ag bound to adaptive, Ag-specific Abs, sensitization of NK cells could be triggered by binding of polyspecific natural Abs to viral particles. The author postulates that in case of CoV infection, binding of polyspecific natural Abs (e.g., B1 cell-derived IgM) to CoV particles mediates presentation of CoV-derived antigenic patterns on the surface of Ag-presenting cells and that the latter are recognized by NK cells. Although different in nature (‘innate’ instead of ‘adaptive’), it has been equally difficult to design safe and efficient NK-cell based vaccine prototypes. Ideally, the latter should target molecular patterns of virus-associated motifs that are presented at an early stage of infection on the surface of infected cells outside of the MHC class I Ag-binding cleft. Clearly, the challenge to designing such vaccines is not genetic MHC-restriction of Ag-specific immune cells but rather the fact that these virus-associated motifs are still largely unknown. Although ‘non-self’ in nature and exposed on the surface of pathogens or pathologically altered host cells (e.g., virus-infected or cancer cells), these motifs are ignored or not effectively recognized by the host immune system. There is compelling evidence that these motifs are capable of subverting immune recognition of conventional pathogen-derived antigens as of an early stage of natural infection or immune pathogenesis of disease (personal communication). It is postulated that structural mimicry between these pathogen-associated antigens and components of cell surface-expressed Ag-presenting self-molecules or terminal self-glycans underlies the mechanism of immune subversion. It is reasonable to assume that pathogens have evolved such molecular mimicry during their evolutionary adaptation to their natural host. NK cell-based vaccine design aims at unlocking the untapped potential of innate, Ag-nonspecific, MHC-unrestricted NK cells to durably recognise a broad and diversified spectrum of pathogen-associated self-mimicking peptide or glycan determinants. As these determinants exhibit a high level of homology across a broad range of antigenically distinct pathogens (even including phylogenetically unrelated pathogens), NK cell-based vaccines would serve as an invaluable armamentarium for fighting a broad spectrum of emerging diseases. As the immune responses they induce can target several different pathogens at the same time, NK cell-based vaccines would obviate the need for embarking on large-scale manufacturing of new vaccines in the midst of a pandemic. In addition, NK cell-based vaccines that are designed to target pathogen-associated self-mimicking motifs would exploit immune mechanisms that are naturally protective of ‘self’ and hence, be featured by an excellent safety profile. As they are targeting infected or pathologically altered cells, they could even be used in a therapeutic setting (which is, of course, not possible with live vaccines). If designed properly, NK cell-based vaccines would have the unprecedented potential to meet medical needs for which prevention or treatment is currently not feasible or highly cost-ineffective and significantly contribute to leveraging pandemic preparedness.

Of course, vaccine manufacturers claim they are already in the process of ‘updating’ their vaccines in order for those to better match the antigenic constellation of the more infectious variants. However, it is difficult to imagine how this could solve the above-described problem of immune escape variants. First, they will need to strengthen adjuvantation of the S-targeted vaccines to overcome the well-known ‘antigenic sin’ issue and allow for epitope spreading such as to cover more Sars-CoV-2 variants (9). However, adding new adjuvants to vaccines has been the single most important stumbling block in modern vaccinology. But even more importantly, the virus will continue to evolve towards enhanced infectiousness and vaccine resistance as long as the conditions for those evolutionary dynamics are fulfilled, i.e., as long as vaccines that cannot block transmission are used in mass vaccination campaigns conducted in the heat of a pandemic of a highly mutable virus.

Theoretical options for safe and efficient immune interventions that are not at risk of causing viral resistance to the vaccine when deployed during a pandemic of Covid-19 variants (options currently available are in bold):

Theoretically, components of the multidrug early treatment kit (e.g., ivermectin) could also be used during a limited period of time to drastically reduce viral infectious pressure in any given population. Provided all healthy, non-vaccinated people and, even more importantly, all vaccinees would take the drug around the same time according to the prescribed regimen, the infectious pressure may rapidly drop beneath the threshold required for the virus to transmit and replicate. But even before that happens, the decrease in infectious pressure would already reduce the risk for healthy, non-vaccinated people to contract Covid-19 disease. While having a curative effect in those who contracted the disease and abrogating infection in vaccinated spreaders, antiviral drug treatment administered during a pandemic would also serve as chemoprophylaxis to those who have not yet been infected or who cleared a previous infection. Based upon successes reported for infection and treatment immunizations against parasites, it is not unreasonable to speculate that antiviral chemoprophylaxis in susceptible individuals followed by exposure to circulating Sars-CoV-2 variants provides broad and long-lived protective immunity.

Ideally, drug treatment should be flanked by stringent infection prevention measures, or even a lockdown, for about two months to further diminish viral transmission in general and, in particular, to further diminish the likelihood that non-vaccinated people become re-infected while being highly susceptible(1) to Covid-19 disease. It might not be possible, however, to use any of the currently proposed virucidal drugs on a long-term chemoprophylactic basis if there is a scientific rationale to believe that this could cause drug-resistant variants to reproduce more effectively. To bring the global COVID-19 pandemic under control, it may, therefore, be critical to coordinate and implement a drug treatment program globally but only during a limited period of time, rather than to conduct separate and prolonged drug treatment campaigns in individual countries or regions. There is no guarantee, though, that a single treatment course – even if implemented worldwide - will suffice to eradicate Sars-CoV-2 variants. However, routine monitoring of viral shedding and characterization (not at least in vaccinees!) and recording of those data in a global database would allow for surveillance of viral transmission and evaluation of a potential increase in viral infectiousness before cases of overt Covid-19 disease arise. Depending on the data, Global Health authorities could decide upon repeating this treatment within a few months. Once the pandemic is under control, national public health authorities may envisage a single, large scale treatment campaign in places/ regions reporting active transmission of virus evolving a higher level of infectiousness. Short-term courses of drug treatment may need to be repeated on a yearly or seasonal basis, depending on the local evolution of viral transmission dynamics. This, together with reasonable infection prevention measures (e.g., no mass gatherings and avoidance of overcrowding in general; raising awareness about personal and environmental hygiene), should allow keeping viral transmission rates low enough to prevent breeding of more infectious variants and resurgence of cases of Covid-19 disease in the absence of sufficient herd immunity. Such a strategy may make much more sense than imposing travel restrictions and adhering to complex, time-consuming and costly infection containment measures (e.g., quarantine, contact tracing, elaborated testing procedures, localized lockdowns etc.) that are currently implemented in a number of countries with low transmission rates in an attempt to stamp out flare-ups (e.g., China).

Conclusive remarks:

A steadily growing community of world-class scientists and experts keep calling for an immediate halt to the mass vaccination campaigns as the single most important global health emergency of international concern. At the same time and with the same level of urgency, they urge regulatory and health authorities to officially recognize and promote sequential multidrug treatment as medical standard of care for dealing with Covid-19 disease. Early treatment, as established by P. McCullough and others, should now be made widely available as it has proven highly efficient, practical and cost-effective. Treating Covid-19 patients at an early stage of disease has been shown to dramatically mitigate the current Covid-19 crisis by saving numerous lives and reducing the burden of hospitalizations very substantially. As post-infection treatment intervention, early treatment would also more rapidly provide patients with strong and long-lived protective immunity against Covid-19 and hence, readily contribute to growing herd immunity. Improved, vaccine-based immune interventions will take more time but should be further explored as quick ‘updates’ of the current Covid-19 vaccines will most likely fail to solve the pandemic because they are still based on the very same immunological concept and mechanism. Because those don’t address the risk of evolutionary immune escape, predominant circulation of more infectious and eventually vaccine-resistant viral variants is inevitable. In this regard, the vaccine community may want to focus more on developing vaccines with transmission-blocking capacity and which elicit immune responses that are not prone to antigenic sin. In the highly likely event that upon continued mass vaccination Sars-CoV-2 will eventually become resistant to the current Covid-19 vaccines, such a novel type of vaccines will be required to protect all those previously immunized with any of these vaccines. Since there is also a clear need for a more comprehensive pandemic preparedness, the scientific and vaccine community may want to consider developing vaccine concepts that are capable of tapping into the potential of NK cells as the latter have the capacity to recognize a broad spectrum of pathogen-associated patterns.

Until we develop vaccines that are capable of controlling Covid-19 without generating pockets of immunity that are prone to promoting enhanced viral infectiousness, we may need to rely on a short but large scale course of antiviral drug treatment using a safe, efficient and cost-effective compound that can be made available in high quantities at low cost (this is for experts to decide but is seems like ivermectin would qualify). A well-coordinated and targeted drug treatment program could be a game-changer and turn the tide of this pandemic in that it could drastically reduce the chain of viral transmission, not at least in vaccinees. Whether sensibly targeted virucidal chemoprophylaxis will provide populations with sustained protection from Covid-19 in the post-pandemic era and hence, serve as a full-fledged substitute for herd immunity is likely but unproven. Virucidal chemoprophylaxis seems, however, a promising option, the effectiveness of which could rapidly be explored at low cost and without raising the type of safety concerns that are associated with the ongoing mass vaccination campaigns.











(1) Healthy persons may become more susceptible to Covid-19 disease when their natural, CoV-nonspecific Abs are suppressed by short-lived S-specific Abs from a previous, symptomless infection.

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