Will covid-19 vaccines save lives? Current trials aren’t designed to tell usBMJ 2020; 371 doi: https://doi.org/10.1136/bmj.m4037 (Published 21 October 2020) Cite this as: BMJ 2020;371:m4037
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Integration of epidemiological and experimental data suggests an initial onset of antibody-dependent enhancement of SARS-CoV-2 infection in UK vaccinated young adults
Peter Doshi has raised some concerns regarding SARS-CoV-2 vaccine effectiveness and adverse effects. To shed more light on some of these issues, I try to interpret the evolution of UK epidemiological data on the basis of natural selection and immune biological mechanisms.
To counter viral pandemic infections, two different medical approaches have been pursued: mass and “precision-like” medicine applied to poliovirus and influenza infections, respectively. Mass vaccination against SARS-CoV-2 is now able to reduce symptom severity; however, infection transmissibility was only temporary curbed. First data showed that new generation vaccines were highly effective providing >94-90% protection from infection (not from severe disease). This allowed to promise first herd immunity and subsequently reduction of virus transmission. Unfortunately, vaccine protection from SARS-CoV-2 infection has waned over time, and now a mostly vaccinated (73-87% with two doses) group of UK “young” adults (40-59 years old) has an average probability to be infected more than twice higher than unvaccinated counterpart. A relative increase of infection probability that surprisingly is not observable in older age groups (70+ years old). Notably, longitudinal studies of the same vaccinated or unvaccinated groups can minimise the bias of comparison between groups because the choice to be tested, risk behaviours and infection risk correlated with age, social interactions, occupation or comorbidities are expected to be relatively constant over time within each group. Nevertheless, a significant increase of infections (+ 81%) for these vaccinated “young” adults was recorded from report week 36 to 49.[2,3] During the same time period, unvaccinated counterpart had only a marginal increase of infections (+ 13%), finally leading to half infection probability respect to vaccinated ones.[2,3] Infection probability in vaccinated people losing vaccine-induced immune protection is expected to be similar, not significantly superior to that of unvaccinated counterpart. Moreover, UK “young” adults with strong baseline immunity were vaccinated more recently than the elderly, suggesting that higher immune responses against wild-type spike protein may increase infection probability. This phenomenon calls to mind antibody dependent enhancement of infection (ADE) that might be consequent to progressive both loss of recognition by neutralising immune responses and increase of infection-enhancing antibody affinity. Indeed, due to vaccine-induced immune selection of variants among the numerous available during a pandemic, those not only evading but also exploiting vaccine-induced immune responses have a strong competitive advantage of transmission among vaccinated people and consequently among a whole population when most of it is vaccinated. Is there any evidence in support of this interpretation of epidemiological data?
Two recent reports have described antibodies isolated from severe COVID-19 patients which were able to both bind to a specific epitope of the spike and enhance virus binding to ACE2 and infection.[4,5] Moreover, one of these infection-enhancing antibodies has been shown to display a higher affinity for spike proteins of two Delta variants than for the ancestral SARS-CoV-2 one, suggesting that variants with immunodominant epitopes with higher affinity for infection-enhancing antibodies and for relative B memory cells are possibly positively selected. In this regard, long-lived both B and T memory cells are induced by two mRNA vaccine doses,[7,8] thus suggesting that loss of immune effector antibodies/cells may not be the main cause of loss of vaccine protection and rather that B memory cells might be "exploited" by new vaccine-selected variants. Indeed, new generation vaccines mediate immune responses against only one and highly mutable protein; therefore, the ”homogeneous” pool of immune memory cells generated in response to ancestral spike protein may be easily misled by some SARS-CoV-2 variants carrying specific spike mutated epitopes. This can lead to both a gradual loss of recognition of neutralising immune responses and a higher sensitivity to even a small reduction of these neutralising responses, finally determining a rapid loss of vaccine protection “in vivo”. In this regard, I have recently shown in a longitudinal study that in UK the relative increased risk of symptomatic infection after ChAdOx1 nCoV-19 vaccination was mainly attributable to the emerging Alpha variant carrying specific epitope mutations impairing vaccine-induced neutralising immune responses. Interestingly, the emergent AY.4.2 variant has two specific A222V and Y145H spike mutations, which are respectively either very close to the epitope recognized by infection-enhancing antibodies or inside the epitope recognized by neutralising antibodies, raising the possibility that its rapid emergence may be linked to immune both reduced neutralisation and increased enhancement of infection. This is also in line with the increased infection in young vaccinated adults during AY.4.2 emergence. Notably, a booster dose (or an infection in vaccinated people) induces an immune expansion phase that can increase protection from severe infections because high concentrations of sub-neutralising immune responses prevail on infection-enhancing ones.[4,5] However, during the following immune contraction phase, infection-neutralising immune responses may rapidly reach a non-protective threshold. In this case, if the virus is contracted, infection-enhancing antibodies developed during vaccination and recognising specific epitopes with high affinity in selected variants may be unleashed to induce ADE in vaccinated people. Moreover, variants exploiting vaccine-induced immune responses have a strong competitive advantage of transmission among vaccinated people which can further select more and more aggressive variants specialised against other vaccinated people. On the other hand, mild Omicron variant that is emerged from mostly unvaccinated African countries has an endemic-like traits and might produce a natural and free vaccine-like infection that protects from other aggressive variants rather than be a threat; unfortunately, third dose vaccination with the same old spike sequence has been shown to “protect” people from Omicron infection, possibly leaving more chances of infection to future aggressive variants specialised to infect vaccinated people.
Mass vaccination can be a temporary solution to contain early pandemic phase. Now is time to move forward into a “precision-like” medicine that was successfully applied for highly mutable influenza virus. Only hosts predisposed to severe COVID-19 and identified by prognostic markers have to be pre-threated with vaccines; while infected patients developing strong natural immunity can be treated with anti-inflammatory and/or tailored drugs. In this regard, more specific treatments, such as those targeting ACE2 and ADAM17 activities, has been extensively proposed.[12-14]
1. Doshi P. Will covid-19 vaccines save lives? Current trials aren't designed to tell us. BMJ. 2020;371:m4037. Published 2020 Oct 21. doi:10.1136/bmj.m4037
2. UK Health Security Agency. COVID-19 vaccine surveillance report: Week 49. 2021
3. UK Health Security Agency. COVID-19 vaccine surveillance report: Week 36. 2021
4. Liu Y, Soh WT, Kishikawa JI, et al. An infectivity-enhancing site on the SARS-CoV-2 spike protein targeted by antibodies. Cell. 2021a;184(13):3452-3466.e18. doi:10.1016/j.cell.2021.05.032
5. Li D, Edwards RJ, Manne K, et al. In vitro and in vivo functions of SARS-CoV-2 infection-enhancing and neutralizing antibodies. Cell. 2021;184(16):4203-4219.e32. doi:10.1016/j.cell.2021.06.021
6. Yahi N, Chahinian H, Fantini J. Infection-enhancing anti-SARS-CoV-2 antibodies recognize both the original Wuhan/D614G strain and Delta variants. A potential risk for mass vaccination? J Infect. 2021, S0163-4453(21)00392-3. doi: 10.1016/j.jinf.2021.08.010.
7. Piano Mortari E, Russo C, Vinci MR, et al. Highly Specific Memory B Cells Generation after the 2nd Dose of BNT162b2 Vaccine Compensate for the Decline of Serum Antibodies and Absence of Mucosal IgA. Cells. 2021;10(10):2541. Published 2021 Sep 26. doi:10.3390/cells10102541
8. Guerrera G, Picozza M, D'Orso S, et al. BNT162b2 vaccination induces durable SARS-CoV-2 specific T cells with a stem cell memory phenotype [published online ahead of print, 2021 Nov 2]. Sci Immunol. 2021;eabl5344. doi:10.1126/sciimmunol.abl5344
9. Zamai L, Rocchi MBL. Hypothesis: Possible influence of antivector immunity and SARS-CoV-2 variants on efficacy of ChAdOx1 nCoV-19 vaccine [published online ahead of print, 2021 Jul 31]. Br J Pharmacol. 2021;10.1111/bph.15620. doi:10.1111/bph.15620
10. UK health security agency. SARS-CoV-2 variants of concern and variants under investigation in England. Technical briefing 29.
11. UK health security agency. SARS-CoV-2 variants of concern and variants under investigation in England. Technical briefing 31
12. Zamai L. The Yin and Yang of ACE/ACE2 Pathways: The Rationale for the Use of Renin-Angiotensin System Inhibitors in COVID-19 Patients. Cells. 2020b;9(7):1704. doi:10.3390/cells9071704
13. Zamai L. Upregulation of the Renin-Angiotensin System Pathways and SARS-CoV-2 Infection: The Rationale for the Administration of Zinc-Chelating Agents in COVID-19 Patients. Cells. 2021;10(3):506. doi:10.3390/cells10030506
14. Montanari M, Canonico B, Nordi E, et al. Which ones, when and why should renin-angiotensin system inhibitors work against COVID-19?. Adv Biol Regul. 2021;81:100820. doi:10.1016/j.jbior.2021.100820
Competing interests: No competing interests
Response to Gupta and colleagues
Thank you for your comments.
I would like to address your assertion that "if the mild illness due to any illness is prevented, the serious illness and deaths will also be prevented particularly at a population-level.”
First, I think it is reasonable to say that in a single human, preventing mild illness in that person should prevent that same person from experiencing further progression of the disease, thus preventing severe illness. (Of course there is no guarantee the person would progress to severe illness in the absence of vaccine, but the notion of nipping something in the bud is well taken.)
But it is a different matter to assume that a vaccine’s ability to preventing mild illness in one population (say, generally healthy, younger people) provides us with evidence of the vaccine’s ability to preventing severe illness in a different population (e.g. frail, elderly people). For example, influenza vaccine is well known to have lower efficacy in frail elderly compared to healthy adults. Nobody claims that an influenza vaccine that is 60% effective against lab-confirmed symptomatic influenza in healthy adults implies a 60% reduction against influenza deaths in the elderly.
My concern is as follows: the frail elderly are disproportionately contributing to the serious cases of Covid-19. Yet they were insufficiently recruited into the randomized trials. So we have precious little evidence from the trials on how effective the vaccines are in the very group that stands most to benefit from an effective vaccine.
This concern is not mine alone. The mistake of blindly extrapolating evidence from one population onto a different population for which we have ample reason to think vaccine response may be less robust was raised last October by a member of the U.S. FDA’s advisory committee.
 FDA Vaccines and Related Biological Products Advisory Committee - 10/22/2020. Video: https://youtu.be/1XTiL9rUpkg?t=27169 Transcript: https://www.fda.gov/media/143982/download#page=346
Competing interests: I am the author of the original article; please see that article for a declaration of competing interests.
We agree with the mentioned facts by Peter Doshi.
However, if the mild illness due to any illness is prevented, the serious illness and deaths will also be prevented particularly at a population-level (to my knowledge no study is available to disprove it thus far) . Most trials do not look for reduction in the premature all-cause mortality, albeit a much desired goal; largely because of the limitations of the sample size and the duration of the follow-up. Obviously during this pressing times, it is not possible to enroll huge number of persons and/or to continue with the trials for a much longer period to specifically address the issue of serious illness and deaths.
Therefore, while you are correct with your facts and data, to say that serious illness and deaths are not addressed in the trials; may easily convey an unintended message particularly to a layman that vaccines for Corona-19 are not effective to prevent serious illness and death. This may have serious adverse consequences at population-level, particularly during the ongoing serious pandemic.
Competing interests: No competing interests
Trial experiments and protocols set for COVID-19 vaccination did not take into consideration of many direct and indirect consequences of mass vaccination.
Here I would like to bring attention to an urgent and very important issue of its indirect effect. Apart from the direct side effect after vaccination, if any; the secondary effect that might be caused due to mutation of the virus after mass vaccination needs attention too. After the initiation of vaccine programme, almost all countries experienced a sudden surge of transmission and most countries had to impose strict lockdown measures.
Professor Paul Bieniasz from Rockefeller University, USA, expressed his concern that vaccines themselves can also drive viral mutations and hence COVID-19 vaccines can add fuel to the evolution of mutation of Coronavirus. According to him the time between initial vaccination and the time of second shot to maximize the immune response might serve as a sort of breeding ground for the virus to acquire new mutations .
A highly populated country India was having a steady decrease for five months. India did not have any lockdown. Though neighbouring countries Pakistan and Bangladesh experienced the 2nd wave this winter but India did not. India passed major festive seasons where social distancing was very difficult to be maintained, still cases and deaths continued to decline. Surprisingly, vaccination started on 16th January and from around 16th February, India started showing a rise in cases. Now there is a steep rise in deaths too . As India nearly managed the disease without any vaccine or lockdown, it attracted global attention. However, scientists failed to associate any obvious cause for the sudden surge in the recent period when winter passed. India’s neighbouring countries Pakistan and Bangladesh also started a rise in cases in recent period, after vaccination started, though they already experienced a 2nd wave last winter.
For Brazil, vaccination started in mid-January and a sharp rise in cases is observed since mid-February. Such a steep rise in deaths in Brazil that happened for the last one month never happened in the whole period of pandemic. It already reached twice the height of previous peaks . Globally, the cases started increasing after 5 weeks of a steady decline and coincidentally, the period of rise matches when major vaccination programmes were initiated worldwide. Some countries are now showing a decline, where lockdown and seasonal temperature are playing strong roles. Even for the UK and Israel, where massive vaccination took place, the total deaths in the last three months after vaccination now reached the overall death of the past 10 months before vaccination .
Such observation and analysis raises major worries especially for highly populated developing countries like India, Pakistan, Bangladesh, Brazil and the African continents among others and needs urgent attention.
Competing interests: No competing interests
Peter Doshi’s nuanced article has opened up a rigorous and valuable discussion about the ongoing COVID-19 mRNA vaccine clinical trials, and I would like to home in on what is perhaps the most salient source of concern about their efficacy and safety, and a key step in building public confidence: the need for extensive data on the vaccines' cellular tropism and MHC Class I vs. MHC Class II-mediated antigen presentation, with attendant questions about potential seeding of autoimmunity. The mRNA vaccines’ nucleic acid payload is ferried into human cells via complex lipid nanoparticles (LNPs) with a lipophilic formulation capable of traversing phospholipid bilayers, through endocytosis and other mechanisms . While some LNP vehicles have been engineered with specific tropisms for target tissues, others have less selective tropisms (or are even potentially omnitropic), capable of entering diverse cell types . From studies thus far, it remains unclear under which category the LNPs used in the COVID vaccine trials appear to fall, and this point is essential for gauging long-term safety and efficacy. If these LNPs have a broad cell tropism, then they would be capable of entering and expressing the SARS-CoV-2 viral spike protein within the parenchyma of vital organs and tissues, well beyond the tropism of wild-type coronavirus. The resulting non-self protein, presented to immune surveillance via MHC-I complexes, would trigger a cytotoxic (CD8-mediated) immune response to the expressing cells, which could with time engender clinically significant tissue damage.
To elaborate briefly on this concern, and the data which could alleviate it, we can roughly subdivide the standard pediatric and adult vaccine repertoires into two broad categories, on the basis of the cells that present the vaccine-mediated antigen to T-lymphocytes. Inactivated virus vaccines (such as Hepatitis A and IPV) and protein subunit vaccines (Hib, Hepatitis B, pertussis) involve primarily MHC-II-based presentation (“Type 1 vaccines” for this discussion). Their antigenic material is taken up principally via phagocytosis by antigen-presenting cells (APCs), particularly dendritic cells in visceral and peripheral tissues, which migrate to lymph nodes and present immunostimulatory epitopes in complex with MHC-II cell-surface molecules to CD4-expressing T-cells (T helper cells), which in turn help to initiate and coordinate the adaptive immune response to pathogens exhibiting the antigen. A cytotoxic response is not induced against the APCs utilizing the MHC-II pathway. Attenuated virus vaccines such as MMR (“Type 2”) enlist not only MHC-II-expressing APCs, but also the MHC-I antigen-presenting pathway present in almost all cell types which, through a standard cascade of events, triggers a cytotoxic response (mediated by CD8-expressing lymphocytes) against presenting cells and tissues, due to the presence of non-self epitopes. Thus attenuated virus (Type 2) vaccines like MMR do entail some cytotoxicity against infected cells, but still confined to the original tropism of the target virus, with an enhanced immunostimulatory effect.
LNP-containing mRNA vaccines represent a novel Type 3 in this classification: enlisting both MHC-II-mediated (through dendritic cells and other APCs) and cytotoxic MHC-I-mediated immunostimulation, but against a far broader array of MHC-I-presenting cells and tissues than the wild-type virus, particularly for LNPs with unselective tissue tropisms. There is potential for enhanced immunostimulatory impact through this process, but also elevated risk of cytotoxic, inflammatory, and autoimmune effects, even more so if the liposomal particles can traverse the blood-brain barrier to enter, for example, motor neurons or oligodendrocytes (the glial cells targeted in multiple sclerosis). These effects, in turn, depend critically on the organ and tissue profile of the cells that receive the LNPs, translate the mRNA payload, and dock the antigenic protein on MHC-I cell-surface molecules. This is doubly true in the case of COVID-19 in light of the still-evolving picture of SARS-CoV-2 immunology. Immune responses appear to be incremental and fleeting, both for natural and vaccine-mediated immunity, suggesting a likely need for multiple boosters after an initial inoculation. Therefore, if cytotoxic responses to integral tissues are transpiring through MHC-I-mediated presentation of SARS-CoV-2 spike protein, the effects may be at first subclinical, manifesting fully only after successive immunizations over months or years.
At present, relatively little has been reported on the tissue localization of the LNPs used to encase the SARS-CoV-2 spike protein-encoding messenger RNA, and it is vital to have more specific information on precisely where the liposomal nanoparticles are going after injection, both in concurrent animal studies and in the two ongoing mRNA vaccine human trials. This process can be commenced in straightforward fashion through cell culture and animal-based investigations, by supplying mRNA expressing a fluorophoric reporter gene (such as green fluorescent protein) delivered via the same LNP formulations as used in the two vaccine trials, and tracking its ingress into varied cells and tissues. The mRNA vaccines represent a remarkable and promising technology, with potential to expedite the development of immunization protocols for future epidemics, but this promise will evaporate if unanticipated safety issues and side effects emerge to weaken public trust in the new modality. Cellular and tissue localization data on the vaccines’ tissue tropisms, obtained and confirmed across multiple independent laboratories, would constitute a valuable step to reinforce public confidence in this regard.
 doi: 10.1016/j.addr.2016.04.014. Mechanisms of transport of polymeric and lipidic nanoparticles across the intestinal barrier. Ana Beloqui, Anne des Rieux, Véronique Préat. Adv Drug Deliv Rev. 2016 Nov 15;106(Pt B):242-255.
 doi: 10.1016/B978-0-12-391860-4.00012-4. Lipid nanoparticles for drug targeting to the brain. Maria Luisa Bondì , Roberto Di Gesù, and Emanuela Fabiola Craparo. Methods Enzymol. 2012;508:229-51.
Competing interests: No competing interests
A “cough and fever with positive PCR test would suffice” for “meeting the primary endpoint definition”. That threshold at least would not include asymptomatic cases and cases with still smaller symptoms. Most people would rather not cough and have fever even for a day, so to avoid these symptoms is already some kind of success, and could at least offset the inconvenience of “normal” vaccination reactions.
Furthermore, fever is usually a sign of some intensive reactions taking place inside the body, i.e. of larger damage than visible outside. I would rather suggest to actively look for weaker reactions and changes in participants' activity levels, such as breath rate, pulse and physical activity level. Equipping every study participant with smart bracelets (fitness trackers) should indeed be standard for medication studies.
“Our trial will not demonstrate prevention of transmission,” Zaks said, “because in order to do that you have to swab people twice a week for very long periods, and that becomes operationally untenable.”
For 30,000 study participants that swab themselves twice a week, for 20 weeks, 1,200,000 mio. antigen quick tests would be required, with a purchase price of some 10 mio. Pound or Euro. That was certainly “tenable”. Add another 50,000 or less PCR tests to follow up correct and false positives, at a fraction of the cost.
Another indicator of transmission could be Covid-19 prevalence among spouses and other household members of the study participants, an indicator that is essentially available free of charge. This would however work better in the absence of too close spacing of self-tests among study participants.
For the most important endpoint, it should be considered to make studies that would offer mass vaccinations in certain areas, e.g. in different counties, with a preference on areas with relatively low daily exchange with other areas. This could be made after the most highly prioritized individuals have been offered protection across the country. Areas 1, 2 and 3 might obtain vaccine 1, areas 4, 5 and 6 would obtain vaccine 2. Only areas with a high willingness to participate will be admitted, but pairs of counties also should be rather similar for their climate and sociodemographic composition. General “lockdown” rules for activities would be the same in all participating regions at the same point in time, but should be gradually relaxed. A vaccine with a large effect on transmission would result in a quick reduction of case counts in the respective counties.
Box 1: “If efficacy is declared, one possibility is that the thousands of volunteers who received a saline placebo would be offered the active vaccine, in effect ending the period of randomised follow-up.” It was certainly better to offer them a completely different vaccine for Covid-19. As long as large parts of the general population are not offered to obtain vaccination, it is still acceptable to withhold it also from placebo recipients. However, it may be desired to have all study participants vaccinated for them to take part in riskier activities, thus provoking more contact with the virus.
Competing interests: No competing interests
Thank you for your comment. Moderna and Pfizer report that they are using a saline placebo.  So is the AstraZeneca study in the US.  In contrast, one study that is using a non-saline comparator (an alternate vaccine in this case) is the Oxford/AstraZeneca study in the UK.
I have reviewed my article and cannot see any place where I have the facts wrong. Please cite the specific sentence(s) that you believe are inaccurate.
Competing interests: I am the author of the original article.
You need to acknowledge and correct a serious inaccuracy in this article I.e., that the “placebo” recipients in vaccine trials are administered an alternate vaccine - not a saline solution.
Competing interests: No competing interests
“'If the vaccine also allows you to prevent initial infection, that would be great...what I would settle for, and all of my colleagues would settle for, is the primary endpoint to prevent clinically recognizable disease.' ”
Dr Anthony Fauci quoted by Megan Sheets, Daily Mail .
So, what might happen if people have suppressed symptoms but are contagious? And what will doctors tell their patients if vaccines are rolled out as early as next month [2,3].
 Megan Sheets, ‘ Dr Fauci warns that early COVID-19 vaccines will only prevent symptoms from arising - not block infection’, Daily Mail 27 October 2020, https://www.dailymail.co.uk/news/article-8884031/Dr-Fauci-warns-early-CO...
 Zoe Tidman, ‘ Coronavirus: Doctors to be 'put on standby for potential December vaccine rollout'’, The Independent 4 November 2020, https://www.independent.co.uk/news/health/coronavirus-vaccine-uk-when-ro...
[3’] John Stone, ‘ Re: New guidance from the GMC: what constitutes meaningful dialogue? Vaccines are a matter of individual autonomy too’, 20 October 2920, https://www.bmj.com/content/371/bmj.m3933/rr-0
Competing interests: AgeofAutism.com, an on-line daily journal, concerns itself with the potential environmental sources for the proliferation of autism, neurological impairment, immune dysfunction and chronic disease. I receive no payment as UK Editor
There is a fundamental problem with vaccine trials extending beyond short-term that could indavertently lead to a vaccine appearing to be more effective in reducing C-19 severity than it really is. Commercial and political pressures might lead to intentional exploitation of this possibility. Most populations exhibit a seasonal rise in summer of serum 25(OH)D3 . Vitamin D promotes a lower severity of C-19 and lower risk of testing PCR-positive. If vaccine testing protocols fail to be completed (in northern hemisphere populations) before March the results will be void. Likewise trials run south of the equator in Oct-March will embrace the benefits of higher serum 25(OH)D3 that will likely not pertain in UK in winter. The secosteroid hormone D3 has such profound actions upon innate immunity that it should be mandated as a confounding factor in vaccine trials , and controlled for. It follows that extending UK trials beyond March in order to build the numbers should be disallowed. Personally as an ageing biologist I rely upon 4000 IU pd D3 : evolution trumps invention.
Competing interests: No competing interests