Research ProposalPDF Available


  • University of Oxford St Catherine's College


Corona Virus/ Covid-19/ SARS-Cov-2 has ground the world to a halt and is showing up the deficiencies of our health care systems everywhere, and the vulnerability of the global population. When Covid-19 kills, it kills through Acute Respiratory Distress Syndrome/ ARDS which, in effect, kills by a sepsis related process. Thus ARDS is fuelled by the proverbial "cytokine storm" of sepsis. It has also been reported that people who die of Covid 19 ARDS have a depletion of Natural Killer/NK cells,, and that severe cases of Covid-19 have significantly lower T lymphocyte counts with depressed immune function in general [Chen,
Dr Carmen Wheatley D.Phil., St Catherine’s College, Oxford
Corona Virus/ Covid-19/ SARS-Cov-2 has ground the
world to a halt and is showing up the deficiencies of
our health care systems everywhere, and the
vulnerability of the global population.
When Covid-19 kills, it kills through Acute
Respiratory Distress Syndrome/ ARDS which,
in effect, kills by a sepsis related process.
Thus ARDS is fuelled by the proverbial
“cytokine storm” of sepsis. It has also been
reported that people who die of Covid 19 ARDS
have a depletion of Natural Killer/NK cells,,
and that severe cases of Covid-19 have
significantly lower T lymphocyte counts with
depressed immune function in general [Chen,
2020; Tan, 2020; Laing, 2020; Diao, 2019; Kuri-
Cervantes, 2020; Chen, 2020].
At this point in time, when the FDA have suddenly
relaxed many drug control regulations, in order to be
able to use off-label drugs in a desperate attempt to
mitigate disaster, the FDA actually already have
one powerful item in the armoury, to which,
because of its safety and cost-effectiveness, combined
with efficacy, they granted Orphan Drug status some
years ago, for use in suspected terrorist CN gas
attacks. This Orphan Drug is vitamin B12 as
hydroxocobalamin for high dose intravenous
administration, the safest and most efficacious
cyanide antidote on the planet.
Indeed, in countries which use hydroxocobalamin B12
as their cyanide antidote of choice, such as France,
Italy and China, there is more than half a
century’s experience of safe and efficacious
use of high dose cobalamin in the ICU, with a
pharmacological drug safety profile second to
For some time now I have been collaborating with
colleagues at the William Harvey Institute, London,
investigating in animal models the use of high dose IV
cobalamin for sepsis. A key (published) discovery is
that cobalamin is a central regulator of the immune
response, very specifically through timely modulation
of production of the universal second messenger, the
gas nitric oxide/ NO* [Sampaio, 2013]. This time-
dependent regulation of NO* by cobalamin has knock-
on, beneficial, strict regulatory effects on every aspect
of the pro- and anti-inflammatory phases of the
immune response. It ensures the impossibility of a
descent into the unresolved chaos of the
aforementioned “cytokine storms” of SIRS/ARDS/
sepsis and septic shock.
We are now concluding pre-clinical trial work,
defining more precisely the mechanisms by which
high dose IV cobalamin confers protection in SIRS/
sepsis and septic shock.
ARDS is often a feature of sepsis and, as mentioned, is
driven by the self same unresolvable pro-
inflammatory response as sepsis .
Thus our research work is potentially very
applicable to ARDS/ Covid 19 crisis.
In yet to be published work, in which 6 different key
cobalamins were tested, we have discovered that high
dose methylcobalamin B12 is even more
efficacious in an animal model of sepsis than
is high dose hydroxocobalamin B12.
The protocol that I first discussed as potentially
suitable for SIRS/ sepsis/septic shock, -thus ARDS- in
a 2006 Medical Hypotheses paper, [available in full
on my Researchgate page], has been confirmed by our
William Harvey Institute animal model work to be, as
I predicted in 2006, the dose equivalent in a human
of the anti-cyanide hydroxocobalamin B12 treatment.
This treatment already exists in the old Merck
Serono ‘CyanoKit’, (approved also by EMA/ the
European Medicines Agency), and now owned
by Pfizer associated Meridian Medical
Technologies Inc.
Based on our collective research insights, and on my
knowledge of the wider cobalamin lab research, and of
the lost, or forgotten, alternative clinical uses of
cobalamin literature, [going back to the 1950s], I
believe that:
would utilise 4 to 5 GRAMS of
methylcobalamin daily, administered by IV, in
saline, for anywhere between 1 to 5, or even 7
days, depending on response, as the safest and
pote ntially most efficacio us trea t ment
available for viral sepsis related ARDS.
Crystalline methylcobalamin is available
w o r l d w id e f r o m m a n y c om p o u nd i ng
pharmacies, and could be deployed on
compassionate grounds at these doses.
However, where it is impossible to obtain
methylcobalamin for the implementation of this
Pfizer’s Meridian Medical Technologies ‘CyanoKit’,
which is licensed, would be a good second
best. (The only negative is that the Cyanokit supplies
the crystalline HOCbl in 5 gram vials, which may be
rather more than is needed to treat children or low
weight patients, so there could be some waste, which
would be avoided with compounded MeCbl titrated to
weight, which, in any case, is substantially cheaper).
This protocol has already been deployed
clinically in other diverse extreme scenarios:
my draft clinical trial protocol of cobalamin for sepsis
-which is available via Researchgate on request-, gives
references showing high dose IV cobalamin efficacy in
clinical refractory vasoplegic syndrome, both in
cardiac surgery and during liver transplants; in carbon
monoxide/CO, hydrogen sulphide/H2S poisoning;
and nitrous oxide/N2O poisoning.
More pertinent to the way that Covid-19 kills, and how
high dose parenteral cobalamin can combat this, is the
known fact that cobalamin boosts Natural Killer
c e l l l e v e l s , i n c r e a s e s e f f i c i e n c y o f
phagocytosis, and is critical for the regulated
pro-inflammatory and anti-inflammatory
sequence of the immune response.
A forgotten literature also shows that high dose
parenteral cobalamin has antiviral actions,
includin g against HIV, (for whi ch t he
mechanism has been elucidated [Weinberg,
1995]), and it was used with clinical success in
Japan and in several European countries,
primarily Italy, to treat hepatitis between 1950
to the 1970s. The general immune regulating effects
of cobalamin have been demonstrated both in vitro,
and in clinical studies some of which go back decades.
[For extensive references in support of all the above
statements, please see my imminent allied
Researchgate pre-print to be posted in March 2021:
The Effects of Cobalamin on the Immune
Moreover, in 2008, some B12 chemists from South
Africa published a landmark study showing that
cobalamins have direct anti-malarial action, up to 40
times stronger than chloroquine [Chemaly, 2008].
Whilst chloroquine may now have a questionmark
over it given its possible cardiac and other toxicity
issues, cobalamin has no toxicity issues, and could
also have an analogous direct effect on the SARS-Cov2
virus, since it is known to bind to RNA aptamers
[Lorsch, 1994].
Thus, all indications from the WHI research are that
methylcobalamin, is a rescue treament well worth
trying now
for the worldwide Covid-19 ARDS crisis.
There is nothing to lose and everything to gain.
Moreover, high dose methylcobalamin could also be
safely and easily deployed at lower high doses, by
intramuscular injection, -as per my draft
methylcobalamin for sepsis clinical protocol, - as
both a potential prophylactic, and a mitigating
treatment for Covid 19 cases that end up in
hospital, to prevent such patients proceeding
to full blown ARDS.
This would obviously take huge pressure off
our collapsing health systems worldwide.
NB Extensive Pharmacological Safety References,
dating back more than half a century, for the
clinical use of High Dose IV Hydroxocobalamin
B12 are included in my
draft Methylcobalamin for Sepsis prophylaxis and
treatment clinical trial protocol.
This B12 cobalamin sepsis protocol is now
available on my Researchgate page as work in
progress, and can be see on request.
If you wish to contact me more directly to discuss
implementation of this potential therapy, please email
me on:
I will be happy to help any doctor anywhere with the
compassionate grounds use of cobalamin for Covid-19.
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Tan, L. et al. Lymphopenia predicts disease severity of COVID-19: a
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Laing, A. G. et al. A consensus Covid-19 immune signature
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perturbations associated with severe COVID-19. Sci. Immunol. 5,
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inflammation, Inflammation in Disease: Mechanisms and
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ResearchGate has not been able to resolve any citations for this publication.
Full-text available
Protein malnutrition has a negative effect on body composition and some blood parameters, especially in the young growing organism. One of nutritional factors which could protect against negative consequences of protein deficiency may be B group vitamins. The aim of the study was to investigate the effect of vitamin B12 supplementation on the immune system in rats fed a standard and a low-protein diet. Rats were fed a control (20% of energy from protein) or a protein-deficient diet (4.5% of energy from protein). Half of animals in each group were additionally supplemented with vitamin B12 (300% of the daily intake). The white blood cells analysis and lymphocytes immunophenotyping (number and percentage) were performed. Low-protein diets caused disturbances in WBC and lymphocyte subpopulations in both short- (30-day) as well as long-term periods (90-day). Vitamin B12 supplementation significantly reduced the negative impact of protein malnutrition after 30 days, however had no effect on long-term malnutrition. Furthermore, vitamin B12 addition in rats fed a control diet did not affect the studied parameters. This observation opens the promise of use of vitamin B12 supplementation to improve immune system parameters in protein malnourished organisms.
Full-text available
Different vitamin B12 and folic acid concentrations could exacerbate the immune response. The aim was to evaluate different dietary folic acid and vitamin B12 levels on the immune response in aged rats. Male Sprague Dawley aged rats were assigned to three folic acid groups (deficient, control, supplemented) each in absence of vitamin B12 for 30 days. Several parameters of innate and acquired immune responses were measured. Serum and hepatic folate levels increased according to folic acid dietary level, while vitamin B12 levels decreased. There was a significant decrease in natural killer cell-mediated cytotoxicity in the spleen for the vitamin B12 deficient diet and folic acid control diet groups. Significant changes in CD45 lymphocyte subsets were also observed according to dietary imbalance. Lymphoproliferative response to concanavalin A and phytohemagglutinin did not differ significantly between groups. The spleen response to lipopolysaccharide increased significantly, but was unmodified for the other organs. An imbalance between dietary vitamin B12 and folic acid concentrations alters some immunological parameters in aged rats. Therefore, the ratio between folate and vitamin B12 could be as important as their absolute dietary concentrations.
Full-text available
Lymphocyte subpopulations and intrinsic factor and gastric parietal cell antibodies have been measured in 23 patients with megaloblastic anaemia who responded to treatment with hydroxocobalamin. The ratio of helper (OKT4) to suppressor (OKT8) lymphocytes was significantly increased in patients with intrinsic factor antibody compared with those who lacked the antibody. No such correlation was found for gastric parietal cell antibody. Alterations in the lymphocyte helper to suppressor (OKT4:OKT8) ratio may be associated with pernicious anaemia.
Full-text available
Lymphocyte transformation responses to the mitogen phytohemagglutinin (PHA) were measured in 20 patients with proven pernicious anemia (PA) and 20 matched controls using 3H thymidine label. The patients with PA showed significant depression of lymphocyte transformation to the 3 doses of PHA employed, as judged by beta counting; however, radioautographic examination of PHA stimulated cells indicated that the results were due to a failure of intranuclear incorporation of 3H thymidine by PA lymphocytes, rather than a failure of PHA to induce blastogenesis. The percentages and numbers of T and B lymphocytes in peripheral blood were measured in 30 patients and controls by rosette and immunofluorescence techniques, respectively. There was no significant difference in the B cell subpopulations between patients and controls; the T cell subpopulation was slightly lower in the PA patients (mean 62.4%) than in the controls (mean 65.5%), but the difference was not statistically significant. The depressed uptake of 3H thymidine by stimulated lymphocytes in PA would seem to reflect a chemical defect rather than inherent immunologic abnormality.
Because an immunological defect of an unknown nature is thought to be a factor in the pathogenesis of pernicious anemia, we studied lymphocyte surface phenotypes in 40 patients and compared them with 113 healthy controls. The only significant difference that emerged was in their slightly decreased number and proportion of surface immunoglobulin (lambda chain) -bearing cells. Of specific interest, the numbers of OKT4+ and OKT8+ lymphocytes and the T4+/T8+ ratios were not significantly different from control values. A sizable minority of patients had increased ratios, while a smaller number had decreased values. No explanation or identifying feature was apparent for those patients with either increased or decreased T4+/T8+ ratios. (One patient with a very low ratio, who was excluded from our analysis, developed acquired immune deficiency syndrome.) No differences were apparent in T4+/T8+ ratios or any other lymphocyte surface phenotypic characteristics when patients were segregated by presence of anti-intrinsic factor antibody or anti-parietal cell antibody, or by race, sex, or age. Our results in a racially heterogeneous group of patients do not support the suggestion that T4+/T8+ ratios are usually abnormal in prenicious anemia or that the presence of anti-intrinsic factor antibody is associated with such abnormality.
A patient with post-gastrectomy megaloblastic anemia is described. Initially, the CD4/CD8 ratio of blood cells was abnormally high and the level of natural killer cell activity was markedly low. These abnormalities were, however, restored by vitamin B12 treatment. Taken together with our prior report on a patient with pernicious anemia in whom the decreased level of CD8-positive blood cells was corrected by vitamin B12 therapy, it may be considered that the reversible CD4/CD8 imbalance of blood cells noted in some cases of pernicious anemia is not pathognomonic for the disease but secondary to vitamin B12 deficiency.
We reported 3 patients with pernicious anemia associated with chronic thyroiditis and evaluated their immunological abnormalities in this paper. Two patients were females and another was male. They were all advanced in age. Levels of gammaglobulin including IgG was elevated in patients' sera. Values of complement components were within normal ranges. Although organ specific autoantibodies against intrinsic factors, parietal cells and thyroidal tissue antigens were detected, organ non-specific autoantibodies such as anti-DNA and/or anti-ENA antibodies were negative in the patients' sera. Percentage of T cells in peripheral blood remained within normal ranges. However, ratio of helper T/suppressor T cells was reduced considering patients' age. Moreover, Mantoux tests were negative in all of three patients. These results suggested that impaired cellular immunity, particularly imbalance of T cell subsets, caused by senescence, simultaneously induced pernicious anemia and chronic thyroiditis in these patients.
Lymphocyte subpopulations were measured in the blood of 17 patients with megaloblastic anaemia due to vitamin B-12 deficiency. 14 patients had pernicious anaemia and 3 others were gastrectomized. By using monoclonal antibodies recognizing T cell surface markers and immunofluorescence microscopy, we found a significant decrease in the number of circulating suppressor T cells and an increase in the ratio of helper to suppressor T lymphocytes in pernicious anaemia patients. This finding may be related to other immune abnormalities found in pernicious anaemia, e.g. the presence of multiple autoantibodies.
A unique case of pernicious anemia is described. Initially, the percentage of OKT8-positive blood cells was markedly decreased, resulting in an increase in the OKT4/OKT8 ratio. The level of OKT8-positive blood cells was, however, returned to normal after vitamin B12 therapy. The finding may propose a possible role of the imbalance of blood lymphocyte subpopulations on the pathogenesis of pernicious anemia and also a responsibility of vitamin B12 for such a selective reduction in the OKT8-positive blood cells.