Bernal JL, Andrews N, Gower C Effectiveness of Covid-19 vaccines against the B.1.617.2 (Delta) variant. N Engl J Med. 2021; 385:585-594 https://doi.org/10.1056/NEJMoa210889
Griffin JB, Haddix M, Danza P SARS-CoV-2 infections and hospitalizations among persons aged ≥16 years, by vaccination status – Los Angeles County, California, May 1–July 25, 2021. MMWR Morb Mortal Wkly Rep. 2021; 70:1170-1176 https://doi.org/10.15585/mmwr.mm7034e5
Gostic KM, Bridge R, Brady S Childhood immune imprinting to influenza A shapes birth year-specific risk during seasonal H1N1 and H3N2 epidemics. PLoS Pathog. 2019; 15 https://doi.org/10.1371/journal.ppat.1008109
Wagner A, Weinberger B. Vaccines to prevent infectious diseases in the older population: immunological challenges and future perspectives. Front Immunol. 2020; 11 https://doi.org/10.3389/fimmu.2020.00717
The coronavirus disease 2019 (COVID-19) vaccine story is continuously unfolding. Since our previous COVID-19 commentaries, much new information has transpired on the subject, and here we revisit this topic, which has practical implications for all stakeholders in dentistry, as well as the public. This article, on current vaccine epidemiology, provides an account of why vaccines fail in general, and the particular concerns in relation to the new Delta variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and related ‘variants of concern’. Issues related to vaccine failure are fundamentally dichotomous in nature, appertaining either to the vaccine strain (type) per se, and/or the numerous endogenous factors of the vaccine recipient/vaccinee. Societal factors such as vaccine hesitancy and its impact on herd immunity appear to overarch the long-term goal of total or partial global suppression of SARS-CoV-2, and its eventual endemicity.
CPD/Clinical Relevance: To describe the reasons for the failure of currently administered COVID-19 vaccines, particularly in relation to the advent of the SARS-CoV-2 ‘variants of concern’, and discuss implications for clinical dental practice.
Article
The biggest vaccination campaign in human history is ongoing. The battle against coronavirus disease 2019 (COVID-19) is virtually halfway through, with an armamentarium of vaccines, antivirals and other drugs, and an array of societal preventive measures. These have led to a global decrease in the COVID-19 numbers with a few pockets of higher morbidity and mortality. COVID-19 vaccines continue to lower the risk for severe COVID-19 disease, hospitalization and death, even against the more virulent Delta variant.1 Efficacious deployment of COVID-19 vaccines has offered humanity quick access to its endemicity. Since the first vaccine was administered in December 2020 in the UK, some 3.9 billion people have at least had a single shot, and 2.9 billion are fully vaccinated worldwide (as of 23 October 2021).2 This, together with those who have survived the infection, implies that about half of all people worldwide are likely to be immune to the disease today. Dental care workers, as frontline health professionals, were the earliest recipients of the vaccine, and some, in certain jurisdictions, were actively involved in the administration of vaccines as well. It is now highly likely that the annual vaccination schedule for dental healthcare workers (DHCW) will incorporate a compulsory COVID-19 vaccine.
Currently, there are eight different approved COVID-19 vaccines and a further 14 are authorized for limited use, while 32 have undergone Phase 3 trials and are awaiting approval by health authorities.3 Despite the availability of vaccines, their delivery and uptake is totally skewed depending on geographic region, with some poorer countries having less than 5% vaccinated in contrast to some regions where almost the whole population has been vaccinated, such as UAE.2 Hence, we are not out of the woods yet. There are several pitfalls ahead prior to reaching the end goal, now considered to be the global endemicity of the virus into the foreseeable future.
The waning immunity of the vaccinees, and the consequent need for booster doses, the reported vagaries of the increasing number of brand-name vaccines, the purported or real, vaccine adverse effects, the possible emergence of vaccine-resistant viral variants (so-called ‘variants of concern’, in contrast to the ‘variants of interest’), the adverse publicity in mass media on the unfounded perils of the vaccines, and low uptake are all contributing to this phenomenon. This COVID Commentary addresses some of these issues, particularly why the vaccines differ in their efficacy, and provides an update (Table 1) on the current vaccine recommendations by the World Health Organization (WHO) and the US Centres for Disease Control and Prevention (CDC).
Pfizer
Moderna
AstraZeneca
Johnson & Johnson
Vaccine platform
mRNA in lipid nano-particles
mRNA in lipid nano-particles
Non-replicating human adenovirus-based
Non-replicating human adenovirus-based
Required doses
Two doses, 3 weeks apart
Two doses, 4 weeks apart
Two doses, 1 month apart
One dose; two doses desirable (pending formal approval)
Approval date/pending approval
Given full FDA approval 23 August 2021
18 December 2020
WHO approval on 21 February 2021
Approval on 27 February 2021 for emergency use
Efficacy (percentage protected after full dosage)
95% in adults; 93% in 12–18 year olds in US vaccinees; 90% effective in 5–11 year olds
94.1% adults
70% adults
66.1% globally; 72% in the US; 86% effective against severe disease
Recommended age group
12 years and older
18 years and older
Pending
18 years and older
Eligibility for a booster shot
8 months after second dose
8 months after second dose; approved by FDA (October 2020)
To be determined
Approved by FDA (October 2020). Heterologous booster preferred >65 years
Common side-effects
Fatigue, headache, chills, muscle pain, especially after the second dose
Fever, muscle aches, headaches lasting a few days. Effects worse after second dose
Pain in vaccine site, fever, muscle aches, headache
Pain in vaccine site, headache, fatigue, muscle pain
FDA warnings of adverse side-effects
Cardiomyopathy, especially in children (over 1000 cases reported)
Cardiomyopathy, especially in children (over 1000 cases reported)
–
Increased risk for developing Guillain–Barré syndrome
Extremely rare side-effects
Anaphylaxis, Bell's palsy
Anaphylaxis, Bell's palsy
Transverse myelitis (two cases thus far); VITT or blood clotting in combination with/without a low platelet count
VITT or blood clotting in combination with/without a low platelet count (1:100,0000)
Note: all of the current vaccines prevent hospitalization from the disease (except in rare cases); none of the vaccines interacts with recipients cellular DNA.
VITT: vaccine-induced thrombotic thrombocytopenia. Data from various sources (as of 25 October 2021).
Current vaccine epidemiology
The recurrent waves of COVID infections we are witnessing now, particularly in the developed world where vaccines are readily available, have been termed the ‘pandemic of the unvaccinated’ because it is estimated that the unvaccinated are 11 times more likely to die than those fully vaccinated.4 Additionally, the new viral variants of concern, such as the Delta variant of SARS-CoV-2 and its subvariant AY strain, have caused renewed outbreaks even among the vaccinated cohorts.
It has been estimated that people who are infected with the Delta variant can spread the virus to between 5 and 9.5 other people. This number, termed the basic reproductive number, called R0 or R nought, is the average number of susceptible people that each infected person is expected to infect. R0 of the Delta variant is higher than the original virus identified in Wuhan, China, which had an R0 of between 2.3 and 2.7, and the Alpha variant (previously, the UK variant), which had an R0 of between 4 and 5. The Delta variant can be as infectious as chicken pox, which has an R0 between 9 and 10.5
In brief, the reasons for the rapid spread of the new delta variant are four-fold: (i) the increased contagious window; (ii) increased viral shedding, at least twice as many virions as the original strain; (iii) increased environmental stability; and lastly, (iv) the increased avidity (binding) of the variant to the host receptor cells in the oropharynx and the lungs (Figure 1).5 Consequently, the Delta variant is the predominant strain in most of the West, including UK and US, and in other regions such as India and South East Asia.6 Unfortunately, even among the fully vaccinated for COVID-19, this variant may cause asymptomatic or mild illness, thus creating vicious cycles of covert disease spread to others. Nonetheless, almost all of the current COVID-19 vaccines appear effective at preventing hospitalization and death among even those who contract the variant-induced disease (Table 1).
Figure 1. Four major reasons for the rapid global spread of the Delta variant of COVID-19 in comparison to its parental strain; ACE 2, angiotensin converting enzyme 2. (Figure created using Biorender.com software)
In general, the vaccine efficacy varies from one vaccine to another, ranging from approximately 50% to 95% for the widely available strains of COVID-19 vaccines and depends on a variety of factors.7 Vaccine efficacy is simply defined as the percentage reduction of disease in a vaccinated group of individuals compared with an unvaccinated group under similar conditions in a vaccine trial ecosystem.8 The term is often confused with vaccine effectiveness (formerly called ‘field efficacy’), which is used to describe how a vaccine reduces the disease in a vaccinated population over a substantive period, given the constraints associated with vaccine delivery such as cold chain logistics, access to healthcare and the vaccine cost.9 This said, the two terms, vaccine efficacy, and vaccine effectiveness are synonymously, and interchangeably used in numerous contemporary reports and in the media.
Vaccine efficacy can never be 100% in a given population. Hence, it is clear that a significant proportion of the COVID-19 vaccinees will not fully seroconvert, meaning that the required level of antibody needed for protection is not reached after the two-dose regimen, a phenomenon called poor or suboptimal seroconversion. Hence, for all practical purposes, especially for clinical professionals, such as dental practitioners, who work in a hazardous environment, there may be a need to establish and ascertain seroconversion status after the standard vaccine by measuring the antibody titre with a serology test, after a specific post-vaccination period.10 One good example of this is the evaluation of antibody levels after receiving all three doses of the hepatitis B surface antigen (HBs) vaccine. If, in the event, antibody levels to HBs are suboptimal (<12 mIU/mL), then the usual practice is to offer an additional dose of the vaccine.11
The latter titre of antibody beyond which the protection against the disease is conferred is called the immune ‘correlate of protection’. Having a correlate of protection would help determine whether protection has been conferred by the vaccination procedure, and allow further actions that could then trigger interventions. Unfortunately, an immunological correlate for COVID-19 has not yet been determined, but is eagerly awaited because this ‘magic number’ will provide a precise cut-off point for the booster dosing, as well as its frequency. This will also help determine the need for booster vaccination programmes on a population-wide basis. A need for such a correlate of protection for COVID-19 and the level of immunity is dictated by the general factors associated with the vaccination procedures, as well as the vaccinees innate response to the vaccine. These are described below (Figure 2).
Figure 2. Factors impacting the efficacy of a vaccine and the depth of the seroconversion; Factors related to the vaccine recipient (vaccinee) are in blue, and those related to the administered vaccine are in grey.
General factors
Vaccine choice (strain selection)
As frontline healthcare workers, dentists are likely to be key decision-makers and opinion leaders on the choice of a vaccine strain (platform), offering advice to their team members and their patients, and the public. The availability of different vaccines on various platforms, with mRNA or dead and attenuated viruses, and traditional or modern technology, in itself, will pose issues in terms of the preferred vaccine for an individual.12 Nevertheless, in the shorter term, due to the current, limited availability of vaccines, this choice is likely to have already been made by the local health or federal health authorities.
However, when different vaccine types are available, it may be incumbent upon the principal employee of a dental practice not only to ensure that all staff members of the practice are successfully vaccinated but also to obtain the necessary information on the available vaccines in the locale and provide specifications and data on the currently offered vaccine strain, its side effects, and other relevant details to his/her employees. Such advocacy should ideally be performed in consultation with the local medical care provider/s and public health consultants depending on the extant policies and procedures of the local dental and health authorities.
Heterologous or mixed-mode vaccination
In this context, mixed-mode or heterologous vaccination of two different strains of vaccines for the primary and the second dose, as well as the booster dose (the third dos, in most vaccine strains) has been widely discussed. Several studies have now confirmed that people who receive two different COVID-19 vaccines belonging to disparate platforms, generate potent, synergistic immune responses, with side effects no worse than those caused by the standard regimens.13 Indeed, heterologous booster dose regimens are highly effective at preventing infection with the Delta strain of the SARS-CoV-2 infection, and exceed the performance of homologous vaccination.13 Although the heterologous vaccination process has passed the efficacy test, questions yet remain, such as the durability of the immune response. (An added advantage of such mixed-mode vaccination is that it supports immunization programmes in lower-income countries, where there might be shortages of vaccines due to disruption of supply chain logistics, for instance).
Vaccine hesitancy
Vaccine hesitancy by the community, in general, has been a subject of much controversy and debate since the introduction of the fist vaccine in the UK for small pox, by Edward Jenner, over two centuries ago.14 Vaccine hesitancy is explained as a delay in acceptance or refusal of vaccination by the community despite the availability of vaccination services.15 The phenomenon is a complex and chronic societal issue, depending on the vaccines in question, and is fuelled by factors such as complacency, and numerous myths, rumours, and fears in the mass media on the disadvantages of the vaccines.15 Additionally, the declarations by a number of religious and political groups devoted to this cause in different parts of the world have not helped popularization of the COVID-19 vaccines and vaccination, in general.
As a key community healthcare provider and the trusted ‘go-to’ person for healthcare information, dental practitioners are in a leadership position to impact the views of their patients and educate and reassure them about the safety of the COVID-19 vaccines and their efficacy, in order to dispel the various myths and fallacies surrounding this critical issue.
Non-responders
The question of the small minority of non-responders to COVID-19 vaccines and how these individuals are managed is another issue that should be addressed according to the extant policies of local jurisdictions. The signs are that the COVID-19 will be a persistent, endemic disease in most regions of the world until the foreseeable future. Hence, the necessity for such measures to protect all stakeholders in dental care-delivery clinics/institutions needs to be resolved and guidelines formulated by the local/federal dental authorities in earnest.
Innate factors related to the vaccinee
A number of innate factors of the vaccinees themselves may lead to an idiosyncratic response to a vaccine, and impact the quality and the durability of the seroconversion. These include general factors such as age, gender, body mass index along with others, such as immune imprinting and immunosenescence, discussed below (Figure 2).
Immune imprinting
Immune imprinting is a phenomenon whereby initial exposure to one virus strain effectively primes the antibody producing, B cell memory and restricts the development of memory B cells and neutralizing antibodies against new minor variant strains of the virus.16 A classic example of this phenomenon is seen in seasonal influenza exposure and the associated vaccine response. This phenomenon is also termed the ‘original antigenic sin’. For instance, childhood influenza exposures leave an immunological imprint, which has a lifelong impact on immune memory cells.16 The fact that elderly people show relatively weak immune protection against influenza, despite seasonal exposure to vaccination against the disease, is indicative of the insufficiency of the antibody responses in adulthood (either through vaccination or exposure to the organism), which do not provide the same strength or durability as the immune response in childhood.
The reasons for the immune imprinting phenomenon are speculative and unclear, as yet. Whether the immune imprinting phenomenon will adversely impact the serological response to COVID-19 vaccines is yet to be determined.
Immune senescence, or immunosenescence
Another reason for waning antibody levels is the age-related disparity in immune response due to so-called immune senescence or immunosenescence,17 which is defined as the gradual weakening of the immune system due to the natural ageing process of an individual. This is exemplified yet again by influenza vaccines, which are less effective in older than in the younger populations. Similarly, older individuals tend to get herpes zoster despite having had childhood chickenpox.18
Systemic diseases and other factors
A number of systemic diseases or conditions may affect the efficacy of vaccines and poor seroconversion after a vaccination program (Table 2). It is now clear that these individuals require a third primary dose (a booster) due to the possibility of breakthrough infections. Additionally they need to continually abide by risk mitigation strategies such as mask wearing and social distancing even after the receipt of a third dose.19 (Note: the issue of booster doses and the frequency of their administration for the general population is still being debated, and not addressed here).
Active haematological malignancies
Non-haematological malignancies with current active treatment, including chemotherapy, radiotherapy and/or hormonal therapy
Solid organ transplant with immunosuppressive therapy
Haematopoietic stem cell transplants (within 2 years of transplantation)
Immunosuppressive therapies
Primary immunodeficiencies
Advanced or untreated HIV infection (those with low CD4 cell counts)
Long-term haemodialysis or peritoneal dialysis
A note on societal factors impacting covid-19 vaccination and its success
Finally, highlighted are two inter-related critical societal and geopolitical issues, vaccine hesitancy (discussed above) and herd immunity, which dictate the success of a global vaccination programs for COVID-19.
As mentioned, vaccine hesitancy is a complex societal problem, fuelled by numerous myths, rumours and fears related to the disadvantages of vaccines. Maintaining public confidence in COVID-19 vaccines, and minimizing vaccine hesitancy will be crucial to eradicate the disease and dental practitioners can play a key contributory role here by educating their patients and the public on the myths and the truths of COVID-19 vaccines. Indeed, WHO has classified vaccine hesitancy as one of top 10 major threats to global health,20 and a critical impediment obstructing the end goal of herd or population immunity.
Herd or population immunity, also known as population immunity, is defined as the indirect protection from an infectious disease that ensues when a population is immune either through vaccination or previous asymptomatic or symptomatic infection.21 The level of vaccination needed to achieve herd immunity varies by disease. It is generally accepted that to reach herd immunity and suppress community transmission of a virus, about 70% of the population would have to be immune. For example, herd immunity against measles needs about 95% of a population to be vaccinated, while the threshold for polio is lower, approximately 80%.22 The proportion of the populace that must be vaccinated against SARS-CoV-2 to induce herd immunity is unknown, as yet. However, experts opine that a 70–80% immune population will abort the disease transmission in the community.21
Only a relatively small proportion of the population has received the full COVID-19 vaccinations currently, which is geographically skewed in any case, and we have a fair way to travel before reaching the goal of global herd immunity for COVID-19. Considering the scientific, societal, and political barriers that must be overcome to achieve this figure of 80% community vaccination, it is dawning on the scientific community that COVID-19 vaccines may not be the panacea for this dreaded disease.23 Hence, at least in the shorter term, continuing to resort to other ancillary mitigating measures, such as mask-wearing, hand hygiene, social distancing, as well as the infection control measures in the clinical ecosystems where DHCWs operate are likely to be critical for COVID-19 prevention.
Conclusions
It is highly likely that a worldwide endemicity of COVID-19 will usher in an era of ‘new normal’ in dentistry. There are a number of critical facets that will mould such modified clinical practice regimens, and a glimmer of this new scenario is emerging with the wide availability of efficacious COVID-19 vaccines. Nevertheless, the dental community need to comprehend that COVID-19 vaccines are but a single device in the overall public health response to the pandemic, and continue to abide by other crucial infection control measures to mitigate SARS-CoV-2 spread, and initiate appropriate administrative and engineering controls in clinical settings, as dictated by either the national or local authorities.
