Chemoprophylaxis against COVID 19 is needed more urgently than ever before (PDF)

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Chemoprophylaxis against COVID-19 is needed more urgently than
ever before

24.05.2020

Downloadable from:

http://freepdfhosting.com/9686575098.pdf

Owing to the situation at the end of May 2020, the need for an effective chemoprophylaxis
against COVID-19-infections (pre-, peri- or postexposure prophylaxis, depending on the
individual situation) is more pressing than ever before.
First, following stagnation at a high level since the beginning of April, the worldwide number
of daily new cases is rising again since about the middle of May.
Second, no progress in treatment and reduction of the mortality rate is evident, in spite of
growing experiences in treatment and rising preparedness of the health care systems. In
Worldometer statistics, the daily number of new deaths is stagnating since the middle of
May, whereas the daily number of new infections is rising. At the first glance, this may look
promising as an indicator for possible therapeutic advances. But there may be other causes
for this divergence between deaths and new cases, for example more testing or changes in
the age structure of newly infected cases. Taking Germany as an example, the age
distribution of newly infected cases changed a lot, and the mean age of new cases fell from
52 years in weeks 15 and 16 to 37 years in weeks 25-27. The mortality (CFR) of the weekly
cohorts fell from 6.8 – 6.9 % (cohorts from week 15 and 16) to 1.2 % (cohort from week 24,
mean age: 38 years) and below (RKI Lagebericht 7.7.2020). In order to find out whether CFR
improved really (and not only as a simple consequence of younger age), age standardization
of CFRs would be inevitable (update).
Third, whereas a lot of hope was associated with (hydroxy-)chloroquine, maybe in
combination with macrolides like azithromycine, it became evident in the second half of
May, based on large trials, systematic reviews and meta-analyses, that hydroxychloroquine
alone or its combination with macrolides is not effective, at least not for routine treatment,
and may even cause harm and increased mortality. This was first suggested by MAGAGNOLI
et al. with their observational and uncontrolled results from older men in American Veterans
hospitals, but in the second half of May, MEHRA et al., SINGH S et al. and IP A et al. (two of
them very large retrospective trials with well-matched controls) as well as CHACKO et al. and
CHANDRASEKAR et al. (both systematic reviews/meta-analyses) showed consistently that
(hydroxy-)chloroquine (or hydroxychloroquine + macrolides) were not associated with any
benefit, at least with regard to important endpoints like mortality. They even may increase
mortality. IP A at al. found a null effect (HRs between 0.99 and 1.02) on in-hospital mortality
in their observational study on 2512 hospitalized patients, among them 1914 with at least
one dose of HCQ and 1473 with HCQ + azithromycine (compared to neither drug).
Moreover, CHANDRASEKAR et al. found no benefit of antiviral treatment (OR 0,83; CI: 0,49 –
1,38), and even remdesivir and Tocilizumab showed only limited success in many trials,
especially in severe or critical disease or in patients already in the ICU or mechanically

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ventilated or even patients on normal wards with a need of oxygen support above FiO2 =
0.5% or more (for remdesivir, e.g. WANG Y et al., SINGH AK et al., ANTINORI et al., LIN TY et
al.; for Tocilizumab, e.g. SANCHEZ-MONTALVA et al., SCIASCIA et al., RIMLAND et al., IP A et
al., GORGOLAS et al. for normal wards ). It is evident meanwhile that none of them is the
“wonder drug” everybody is waiting for, as is sometimes pretended by some media. There is
still no standardized therapy regimen foreseeable which may save people, especially elderly
and people with comorbidities, from severe/critical disease, ICU, mechanical ventilation or
death with a high grade of certainty.
The survival of the critical stages of the disease depends largely on individual luck or fate
with some influence of genetics and epigenetics, for example with regard to alleles or
expression levels of genes relevant for virus susceptibility and, probably much more,
immune response. For example, the most important genetic locus which is associated with
respiratory failure in COVID-19 was inherited from Neandertals, and its frequency varies a lot
between different populations (ZEBERG and PÄÄBO). Age, lifestyle (e.g. smoking, air
pollution), prior infections with other (human) coronaviruses, comorbidities and drugs for
their treatment as well as intestinal microbiota may also influence virus susceptibility or
immune respone either directly or less directly by modulation of gene expression (update).
Fourth, many countries end or reduce their lockdowns and other regulations, rising the risk
of new infections and new superspreading events. Germany, which was very successful with
its lockdown on March 16th, suffered from increasing reproductive numbers in some areas
and new superspreading events already two weeks since some of the restrictions had been
eased.
Beside of this, many people are bored by the restrictions and unwilling to follow them any
more, even if they are maintained.
For people who don’t understand that the end of the lockdown or of special restrictions
which were part of the lockdown is driven primarily by pressing economic demands, they
may misinterpret the end of these regulations as a signal that “danger is gone” and that they
can live and behave as usually again. They don’t understand that the end of lockdown or
particular regulations means nothing else than the delegation of responsibilities from the
government or from local authorities towards each individual (e.g., the responsibility for selfprotection, self-care).
Fifth, as a consequence of these tendencies, even people (like older people or those with
relevant comorbidities) who want to keep on to restrict themselves (like at lockdown times),
and who have good reasons to do so because of their enhanced risk of severe, critical or
deadly disease, may be forced now or soon to participate again in mass gatherings, meetings
and lessons, especially if they are for professional reasons, so that these people cannot deny
to participate (“work kills”). For those people, chemoprophylaxis would be of great
importance.
Sixth, even if an effective vaccine is available one day in the future, how shall so many
people get the vaccine within a short time without “mass gatherings” in medical offices or
other places where vaccinations take place? Strict contact restrictions are incompatible with
mass immunization. However, the protection by the vaccine will start about two weeks after
the (first) dose, so people who get infected at the day of their vaccination won’t be
protected at all. Harmless side effects of vaccination like a little fever, headache, fatigue or

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something like that can imitate COVID-19 disease, and true COVID cases following infections
that occurred during “mass immunization events” may be overlooked as side effects of the
vaccine. Thus during the days around vaccination, social distancing will be very important
once again, but probably the opposite will happen, and many people will think that they are
protected from the moment of injection.
Moreover, it is possible that several doses of the vaccine have to be administered (e.g., three
doses at days 0, 7 and 14 like in the case of PicoVacc [GAO Q et al.]). For the AZD1222
vaccine, a single dose is planned. However, animal experiments showed that a second dose
(boost dose) enhanced the immune response a lot, at least in pigs (update).
Therefore the risk of contacts which are associated with “mass immunization” may indicate
chemoprophylaxis for people with enhanced risk of serious disease, but they must be sure
that this sort of chemoprophylaxis may not interfere with the effectiveness of the vaccine.
Seventh, nobody knows in the moment whether even the “best” of the COVID vaccines in
the future will offer full protection or enough herd immunity to functionally eliminate the
virus from the (local) population. Thus even after mass vaccination, there may be reasons
why certain people with enhanced risks may need chemoprophylaxis in spite of being
vaccinated, if not permanently then in special situations.
Eighth, as pointed out by HASSANI and BENNIS, physical or mental overwork (like stress or
fear of getting or being infected) may enhance susceptibility to infection. Effective
chemoprophylaxis is regarded as a sort of “psychological reinsurance” that can reduce this
stress.
Altogether, there were many unfavorable developments during the last weeks which make
the demand for chemoprophylaxis even much more pressing than it ever was before.
Chemoprophylaxis may be successful in two different ways: it may reduce (or avoid) the risk
of infection, or, when becoming infected in spite of prophylaxis, it may reduce the severity of
the disease (e.g., asymptomatic or mild instead of moderate, severe or critical). The first
effect may reduce the reproduction number R and is therefore of direct epidemiological
relevance, the latter may reduce hospitalization, ICU, ventilation and therefore the demands
for the health care system. In trials about chemoprophylaxis, one should always consider
both endpoints separately. Meanwhile, serological tests at the end of the study may help to
improve understanding the effects of chemoprophylaxis on the risk of infection. Otherwise,
asymptomatic or paucisymptomatic infections can be overlooked.

Current trials about chemoprophylaxis
Until may 13th, there were 88 clinical trials about chemoprophylaxis (pre- or postexposure
prophylaxis or both) registered in the clinical trial database of WHO
(https://www.who.int/ictrp/COVID19-web.csv).
Two of them should have already been finished at that point of time, and one of these two
trials is already published (MENG Z et al.). An overview of these 88 trials is given in a german
language paper, hosted and freely available online
(http://freepdfhosting.com/bedd8b1c79.pdf).

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These 88 trials involve about 200.000 participants; nearly half of them, 95.000, participate in
two large trials about (hydroxy-)chloroquine PREP for health care workers (HCWs) (CROWN
CORONATION and COPCOV). 67 trials (76.1 %) refer to PREP, 25 trials (28.5 %) refer to PEP (a
few of them refer to both PREP and PEP). PEP or combined PREP/PEP trials include 28793
participants; the remaining > 170.000 persons participate in PREP trials. 7 trials with
altogether 11.104 participants include also early (preemptive) treatment of infected or
symptomatic individuals alongside of PEP.
50 trials (56.8 %) are confined to HCWs, further 17 trials (19.3 %) include HCWs beside other
risk groups. 34 trials are planned to be finished until end of October 2020. 12.5 % trials are
from China; so it is unsure whether they can be completed because of the small numbers of
new infections – no new infections, no new exposure risks. PREP/PEP trials don’t work in this
situation.
Beside the two large international PREP HCW trials mentioned above, 29.5 % of trials are
from US, 10.3 % from Spain, 6.8 % from Iran, 4.5 % from Canada, 4.5 % from Australia, 3.4 %
from Denmark und 3.4 % from Egypt, and 2.3 % each from France, Mexico, India and
Pakistan. 86.4 % of the trials are planned to be randomized. Only 30.7 % declare to have
serological testing as one of their endpoints; however, with the progress of serological
technologies and improvements of their specifity and sensitivity, one may hope that more
ongoing trials add serology as one of their endpoints.
Most worrisome, 58 (65.9 %) of the trials are about hydroxychloroquine (HCQ) or
chloroquine (CQ), and only 7 of them combine HCQ/CQ with other components like Zinc or
bromhexine. Another 6 trials (6.8 %) are about BCG immunization of HCWs. All other
candidates for PREP/PEP are explored in only one or two trials, most of them small trials. The
only exception is Russian Arbidol (umifenovir), which is subject of 3 trials. However, all of
these trials are from China and it is therefore very doubtful whether they can be completed,
and one of them is in combination with TCM granules which are not available outside China.
So there is only very little hope that new results can be expected from these trials as far as
umifenovir is concerned.
There are also trials about azithromycine (2x; one in patients with chemotherapy, the other
in combination with HCQ), Lopinavir/Ritonavir (3x; in two trials in direct comparison with
HCQ), levamisole or lsoprinosine or a combination of both (1x), mefloquine (1x), melatonin
(1x) (GARCIA IG et al., TAN and HARDELAND, SHNEIDER et al., ZHANG R et al.), nitazoxanid
(2x), unspecified TCM (5x, one in combination with Arbidol), Tenofovir/Emtricitabine (1x,
compared to HCQ and to HCQ+Tenofovir+Emtricitabine).
Moreover, there are some trials for immunostimulation by Lactobacillus coryniformis K8
capsules (1x) (which also enhances the effects of influenza vaccination in older people and
may be interesting as an adjuvant for older people around the time of COVID vaccination)
[FONOLLA et al.], measles vaccination for HCWs (1x), Mycobacterium-w suspension
intradermal injection (1x), OM-85 capsules (1x), vitamin C (2x in combination with HCQ/CQ),
vitamin D (3x; 1 x alone, 2 x in combination with HCQ) and zinc (3x, always in combination
with HCQ).
Finally, there are a few trials of local chemoprophylaxis of the uppermost respiratory tract by
NO inhalation (1x in HCWs; GIANNI S et al.; for the theory behind NO inhalation, see MARTEL
et al.), NORS (NO releasing suspension) (1x in HCWs), PUL-042, an immunostimulant for

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inhalation with effects on toll-like receptors (1x), Povidone-iodine (1x) and interferon (2x) as
nasal drops or spray.
In summary, if (hydroxy-)chloroquine fails in chemoprophylaxis, or if its protective effects
are only small, there are no alternatives which are well studied in multiple and large trials.
Besides of that, vitamins or immunostimulants may help a little bit at best, but cannot be
expected as highly effective against COVID infection or prevention of severe disease
following infection. For example, true vitamin D deficiency seems to be associated with
increased COVID risks (DARLING et al., DAVIES G et al., MELTZER et al., LAU et al., DE SMET
et al., DANESHKHAH et al., NOTARI und TORRIERI), especially more severe disease (e.g. ICU
need) (PANAGIOTOU et al.), and it was estimated that avoidance of vitamin D deficiency by
vitamin D supplementation may reduce COVID risks by “up to” 15 % (DANESHKHAH et al.).
Based on their in vitro results on SARS-CoV-2 in primary human nasal epithelium cell lines,
MOK et al. suggest to examine a possible role of vitamin D in postexposure prophylaxis (ring
prophylaxis) in contacts of infected people.
So one should already be pleased if trials with vitamins or immunostimulants offer a few
percent of additional protection (which can then be combined with other sub-optimal drugs
for PREP/PEP), if it is statistically significant at all, and it is hard to expect a real breakthrough
by them. Moreover, in the case of immunostimulation, one must be careful not to provoke
excessive reactions of the immune system which may result in enhanced cytokine storms
and other deleterious effects in the case that infection was not successfully suppressed.
With this is mind, the extreme dominance of (hydroxy-)chloroquine in the chemoprophylaxis
trials, and very especially in the larger and more high-grade trials, is extremely risky in case
these trials fail because the lack of true alternatives which are subject to trials of similar size
and quality. As will be discussed later, there are a few promising alternatives to HCQ/CQ, but
none of them is subject of current PREP/PEP trials.
The risk that (hydroxy)-chloroquine may fail increased a lot during the last weeks. Because
the analysis of the trials in the WHO registry mentioned above was performed until May
13th, the ongoing trials about HCQ/CQ were planned and designed at a time when there
were still a lot of hopes associated with (hydroxy-)chloroquine. Meanwhile, in the last weeks
of May, we experienced three developments which are very worrisome:
First, it is demonstrated meanwhile (especially in studies coming in from May 18 th on) that
HCQ doesn’t help in routine therapy, and it may be even harmful and increase mortality. This
is also true for its combination with macrolides, a combination which was associated with
even more hopes (MAGAGNOLI et al., SINGH S et al., CHACKO et al., MEHRA et al.,
CHANDRASEKAR et al., IP et al.).
In the beginning, when the first disappointing results came in, it was still possible to argue
that HCQ/CQ was started too late in these trials and that earlier treatment may help, as was
offered by the Marseille team around Prof. Raoult who reported good success of the
combination HCQ + azithromycine, but preferentially treated young patients (mean age only
43.6 years) with mild disease, and some of them directly after COVID diagnosis (MILLION et
al.). However, the hope for success of HCQ in an early treatment setting was finally
destroyed by the very large study of MEHRA et al. with nearly 15000 patients who got HCQ
or CQ, with or without macrolides, and more than 80000 controls without HCQ/CQ as
partners for precise matching. This study found an increased mortality of about 33 – 45 % for

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all four combinations (HCQ or CQ with or without macrolides) with high statistical
robustness, and, most important, only patients were included in this study who started
HCQ/CQ in the first 48 hours after their COVID diagnosis. As a consequence, this study shows
that HCQ/CQ failed also in an early treatment situation, and this has much more relevance to
the expected effects of HCQ/CQ in PREP/PEP than results from late treatment settings.
The paper of MEHRA et al. was retracted meanwhile because of inconsistencies in their
database. However, this doesn’t change the general conclusions for HCQ because many
other papers have been published or pre-published since the retraction which also show
either uselessness or harm of HCQ/CQ in different study populations, as far as treatment of
manifest COVID-19 disease (usually in hospital) is concerned (update).
Second, MACIAS et al. reported about the 7-week incidence of COVID-19 during the
maximum of the first wave of COVID epidemic in Spain in 722 patients with
autoimmune/rheumatic disease. 290 of them got HCQ as regular treatment for their
underlying disease, mimicking a chemoprophylaxis setting. 1.7 % of patients who took HCQ
and 1.2 % of those who didn’t take HCQ were infected during these 7 weeks, and 1 of the
290 HCQ patients and 2 of the 432 non-HCQ patients was transferred to hospital (none of
them needed ICU). However, there were no serological tests and not all of the presumed
COVID 19 cases could be confirmed by PCR testing because of lack of material. In spite of
these limitations, the results don’t offer any hints in favor of successful chemoprophylaxis by
HCQ. However, exact adherence to HCQ was not studied in this trial. KAUV et al. reported a
case of COVID-19 in a patient who got HCQ (200 mg BID) for SLE. But the blood
concentration of HCQ was found to be very low, suggesting a lack of previous treatment
adherence.
But results from an Israeli healthcare database confirm a null effect of continuous
hydroxychloroquine or colchicine treatment with regard to the results of COVID PCR testing:
among 14.520 people tested, 13.203 were negative and 1317 were positive. 0.25 % of all
test participants took HCQ (0.23 % positive, 0.25 % negative) und 0.49 % took colchicine
(0.53 % positive, 0.48 % negative) (GENDELMAN et al.).
Another study from Spain compared the probability of hospital admission because of COVID
19 in 3951 patients with inflammatory rheumatic diseases; 16.8 % (666) of them got CQ or
HCQ. Their risk of hospitalization because of COVID-19 was not smaller than the risk for
patients without CQ/HCQ (HR for CQ/HCQ: 0.95; CI: 0.5 – 2.1). CQ/HCQ doesn’t seem to
reduce the risk of infection or the severity of the disease in people with inflammatory
rheumatic disease, at least with regard to the endpoint “hospital admission” (FERNANDEZGUTIERREZ et al.).
However, in contrast to FERNANDEZ-GUTIERREZ, KONIG et al. reported about COVID-19
infected patients with SLE from the Global Rheumatology Alliance Registry. As of April 17 th,
80 patients with SLE were reported to be infected with COVID-19, 51 of them used HCQ/CQ.
There was no difference in the proportion of hospitalization between users (57 % = 29/51)
and non-users (55 %; 16/29). 33 % of the SLE patients on CQ/HCQ and 45 % of those without
CQ/HCQ needed any form of oxygen support.

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Based on a large health care data set, 0.29 % of 26.815 SARS-CoV-2-positive people in
Portugal were found to be chronically treated with HCQ (at least 2 g per month on average),
compared to 0.36 % of 333.489 negative persons (p = 0.04). After adjustment for age, sex,
chronic corticosteroids/ immunosuppressants, the aOR for SARS-CoV-2 infection in people
with chronic HCQ treatment was 0.51 (0.37 – 0.70) (FERREIRA et al.). But the authors didn’t
examine dose-effect relationships which would be interesting in a study which found such a
protective effect.

Finally, there are many ongoing trials about HCQ/CQ in PREP or PEP for HCWs, and some of
them are very large. If there are impressive and significant interim results which clearly show
a high protective effect (not necessarily 100 %), one would expect that such results would
have already been announced and celebrated by conventional and social media as “big
breakthrough”. Beside of high media coverage, it would also be necessary for ethical reasons
to communicate such results to the public, provided that they are actually statistically
robust, in order to give other exposed HCWs the chance to protect themselves by such
methods, given that hundreds of thousands or millions of HCWs are under enhanced risk
worldwide in the moment. Moreover, if the success is definitely evident, it could be possible
to unblind the trials and allow participants in the placebo arm to switch to the verum.
Nothing of that happened so far; this is another hint that HCQ/CQ doesn’t seem to work very
well in PREP/PEP. Of course this doesn’t exclude the possibility that it may have some small
or moderate effect; however, then this effect doesn’t seem to be so large and evident that
the study leaders are so sure that they can communicate or celebrate the interim results or
unblind their trials in order to offer protection by verum to everyone.
In an undated paper from the Indian Ministry for Health and Welfare (reference section: see
Ministry for Health and Welfare), there are some informations about a supposed partial
success of HCQ in HCWs in India. HCWs in three hospitals in New Delhi who cared for COVID
patients experienced fewer infections with SARS-CoV-2 themselves if they took HCQ for
prophylaxis. The protective effect is reported to be smaller in HCWs who cared for the
general population. Moreover, another observational study found that, among 334 HCWs
altogether, those 248 who took HCQ for prophylaxis showed lower incidence of SARS-CoV-2
infection after median 6 weeks of follow-up than those who didn’t take HCQ.
However, no precise results were given there or published in a scientific paper. It is not
possible to estimate the quantity of protection and the statistical significance of the results
from this paper. Moreover, if HCQ offered full or largely protection, one would assume that
this would have been described in detail in the paper from the Ministry and/or also in a
scientific paper (for critics, see also: BMJ India correspondent). Altogether, as far as
informations are available from India, these informations suggest that actually there may be
some effect of HCQ prophylaxis in exposed HCWs, but very probably no real breakthrough.
In the first half of June 2020, there was a first report about PREP in HCWs in an Indian
hospital (BHATTACHARYA R et al.). Following an outbreak among HCWs in that hospital
(altogether 28 infections among HCWs), quarantine and COVID testing, there was a chance
to compare PCR positivity rates between 54 HCWs who had opted voluntarily for HCQ PREP
according to the recommendations of the Indian Ministry, and 52 HCWs who didn’t take
HCQ during the critical time interval. 7.5 % of the HCWs who took HCQ were found to be

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infected, compared to 38.5 % who didn’t take HCQ (p < 0.001). Among the 55 HCWs who
had contact with symptomatic infected people (staff), these quotes are 9.38 % vs. 54.55 %,
and among 92 HCWs with face-to-face contacts, they were 7.84 % vs. 39.02 %.
In spite of the impressive and highly significant results, one has to be careful because this
was not a randomized trial and one cannot exclude selection and recall bias; for example,
one cannot exclude the possibility that HCWs who opted for HCQ were more fearful and
thus more careful in their behavior or use of protection. Moreover, both cohorts were very
young (mean age: 26.5 years in die HCQ group, 27.7 years in the control group) and
comorbidities were rare. The authors themselves warn that they cannot prove a causal
relationship between HCQ PREP and COVID incidence in their cohort.
In a second case-control study among Indian HCWs, CHATTERJEE et al. found an adjusted OR
of 0.44 (CI: 0.22 – 0.88) in HCWs who took at least 4 maintenance doses of HCQ (following
loading dose). In India, a loading dose of 400 mg BID and then 400 mg weekly were
recommended to HCWs. The trend between the number of maintenance doses and risk
reduction of COVID-19 was highly significant (p < 0.001). Six or more maintenance doses
were associated with a risk reduction of more than 80 %.
Adjusted ORs: only loading dose „and irregular recall of maintenance“: aOR 1.87 (CI: 0.82 –
4.24); 2 – 3 maintenance doses (MDs): aOR 2.34 (KI: 1.23 – 4.83), 4 – 5 MDs: aOR 0.44 (sign.)
and more than 5 MDs: aOR 0.04 (0.01 – 0.16).
Taken together, 45.5 % of 378 COVID cases among HCWs and 51.75 % of 373 controls had
taken any HCQ (OR 1.28, n.s., p = 0.087). Unadjusted ORs: loading dose „and irregular recall
of maintenance“: OR 1.27 (n.s.); 2 – 3 MDs: OR 1.65 (n.s.), 4 – 5 MDs: OR 0.55 (sign.), more
than 5 MDs: OR 0.19 (sign.).
Among the combinations, HCQ + vitamins was most successful (OR 0.21; CI: 0.08 – 0.52)
(unfortunately, „vitamins“ were not specified), whereas there was a trend that HCQ +
azithromycine + vitamins is unfavorable (OR 1.36; CI: 0.71 – 2.64) (for comparison: HCQ
alone: OR 0.85; CI: 0.62 – 1.17).
The participants of that study were quite young (mean age of cases and controls: 34.7 vs.
33.5 years). Compared to HCWs > 50 years (Ref., OR = 1.00), the protective effect was more
pronounced in the youngest group (18 – 25 years; OR 0.62; n.s.) and the following age group
(26 – 33 years; OR 0.81; n.s.).
KHURANA et al. reported about a COVID-19 outbreak among HCWs in a tertiary hospital in
Delhi. 94 HCWs were infected (mean age: 36 years), 87 were not infected (mean age: 34.3
years). Only 52.1 % of infected HCWs had any symptoms. The authors compared the 22
HCWs who had taken a full course of prophylactic HCQ to the 159 who had taken either an
incomplete course or no HCQ at all and found a significant risk reduction for those who took
the full course (p = 0.012).
However, there was no plausible dose-effect relationship: the proportion of infections was
27.3 % among the 22 HCWs who took the full course, 70.6 % among 68 HCWs who took an
incomplete course of HCQ, but only 44 % among the 91 HCWs who hadn’t taken any HCQ at

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all. The risk of exposure to infected patients was similar for infected and uninfected HCWs,
but infected HCWs more often preferred surgical face masks instead of N95 respirators.
With this confounder and without multiple logistic regressions, the results from KHURANA et
al. are difficult to interprete. There are no informations whether HCQ impacted the severity
of the disease; however, there were only three hospitalisations (one ICU, no death) in the
quite young cohorts at all. It remains unclear whether HCQ may have contributed to that
favorable outcome.
Whereas the Indian „results“ are about PREP, BOULWARE et al. reported on June 3rd the
first ever results of a randomized, placebo-controlled trial with HCQ for PEP. High-dose HCQ
(800 mg loading dose, 600 mg 6 – 8 hours later, then 600 mg/day for the next four days) was
started within 4 days following exposure as PEP for highly or moderately exposed HCWs
(exposed to infected patients or infected staff without adequate PPE) or household contacts
or partners of infected people. The index persons had to be proven COVID-19-positive by
PCR. COVID-19 incidence of the participants was based on reported symptoms within 14
days; PCR testing was performed only in a few of them, so the calculations are based mainly
on symptoms (and thus cannot exclude the possibility of asymptomatic infections).
The trial was stopped following the third interim analysis on May 6th, when 11.8 % of
participants in the HCQ group and 14.3 % in the placebo group were assumed (by the criteria
mentioned above) of being infected. The risk difference of –2.4 % (i.e. 16.8 % relative risk
reduction) was insignificant and not in an acceptable relation to the side effects (40.1 % vs.
16.8 %), so the trial was stopped. Infected people in the HCQ group didn’t profit from milder
disease; instead, they had on average more symptoms, but this may be due to the adverse
effects of HCQ. The risk of hospitalisation was the same for both groups (each: 1 person).
However, there was an association between risk reduction and the time between exposure
and first intake of HCQ. Day 1: 6.5 % vs. 12.7 % (HCQ vs. Placebo), relative risk: - 49 %; day 2:
12.0 % vs. 17.0 %, relativ risk: - 29 %; day 3: 12.2 % vs. 14.5 %; relative risk: - 16 %: day 4: no
risk reduction at all. None of these differences reached statistical significance, but the
tendency is striking. Thinking backwards in time, these results still offer the chance that an
earlier start of HCQ (like in the case of PREP) may possibly offer better results. Thus the
chances of HCQ in a PREP setting are still unsettled and better results with regard to PREP
(compared to PEP) would not be incompatible with the results of BOULWARE et al., though
experiences with HCQ in people with rheumatic or autoimmune diseases point to the
opposite (see above). But it has to be noted again that none of the associatons mentioned
above reached significance because the trial was underpowered to analyse the associations
between COVID incidence and the latency time from exposure to first HCQ intake.
The combination of HCQ with zinc or vitamin C showed no better outcome than zinc or
vitamin C alone. Increased risks for this combination (HCQ + zinc: RR 1.23, n.s.; HCQ +
vitamin C: RR 1.60, CI: 1,12 – 2.28) may be confounded if participants with the highest risk of
infection had a higher probability to take zinc or vitamin C.
Moreover, there is a striking age gradient: young participants (18 – 35 years) did profit more
from HCQ (11.9 % vs. 18.6 % placebo) than middle-aged (36 – 50 years: 11.9 vs. 15.2 %), and
older participants (> 50 years) had an increased risk of COVID-19 in the HCQ group (11.5 %
vs. 5.5 %). Though none of these differences was significant and the trial was underpowered
to resolve this question, the trend is very obvious.

10

Interestingly, household contacts did profit much more (14.4 % vs. 20.8 %) than HCWs (11.3
vs. 12.2 %), though the overall risk for household contacts was higher. Again, there was no
significance.
Unfortunately, in spite of these striking (though insignificant) differences between
subgroups, no multivariate analysis was performed. Maybe there are subgroups who may
profit a lot from HCQ PEP and others who get harmed by it (aside of harms from adverse
effects). Or the striking trends are simply the result of confounding by uneven distribution of
the other variables and would get attenuated by multivariate statistics? Of special interest is
the question of an increased risk for people above 50 years.
Future studies and papers about HCQ in PREP and PEP should perform similar sub-analyses,
but combine them with multivariate calculations to resolve these urgent questions which
suggest that HCQ PEP may be (very?) helpful to some people and (very?) harmful to others.
If only young people profit from HCQ, this wouldn’t help a lot because older people need
PEP much more because of their higher risk of severe or critical disease in the case of
infection. The „age effect“ is especially striking because it was found both in PREP
(CHATTERJEE et al.) and in PEP (BOULWARE et al.). In both trials, the „age effect“ didn’t
reach statistical significance. However, since the trends in both trials point to the same
direction, this has to be seen as a warning that those who need PREP/PEP at most (the
elderly), will profit less (or not at all) from HCQ chemoprophylaxis, and the profit – risk ratio
of HCQ chemoprophylaxis may be age-dependent at the expense of those with the highest
need of protection.
Finally, in their large controlled trial of PEP and preemptive therapy as “ring prophylaxis”,
MITJA et al. showed that neither PEP nor preemptive therapy are successful. With its trial
design and large number or participants, this trial is even more important the the trial of
BOULWARE et al., and may put an end to any hopes about HCQ as PEP and preemptive
therapy; however, the question of PREP is not touched by that trial.
MITJA’s trial emcompassed 2314 participants, among them 2000 PCR-negative when the
trial started (PEP participants) und 314 with positive PCR, but without significant symptoms
(preemptive therapy). The verum participants got HCQ (800 mg at day 1, 400 mg the
following six days); for the control group, there was no placebo. Participants were exposed
health care workers or household contacts of infected people (in the sense of ring
prophylaxis), and workers and residents of nursing homes.
Altogether (n = 2314), 6.2 % of participants in the control arm and 5.7 % of participants in
the HCQ arm developed PCR-confirmed symptomatic COVID-19 (adjusted RR: 0.89; CI: 0.54 –
1.46).
If one restricts analysis to the 2000 participants who were PCR-negative in the beginning
(1042 in the control arm and 958 in the HCQ arm), the rates for PCR-confirmed symptomatic
COVID-19 were 4.3 % (control) and 3.0 % (HCQ). Whereas these data look like a little success,
the adjusted risk ratio shows the opposite (aRR 1.45; CI: 0.73 – 2.88). And if one considers a
more inclusive outcome (either symptoms compatible with COVID 19 or PCR positivity), the
risk was a little higher in the HCQ compared to the control arm (18.7 % vs. 17.8 %; aRR 1.04;
0.77 – 1.81). Finally, at day 14, 14.3 % of the participants in the HCQ group, but only 8.7 % of

11
the control group were seropositive (IgM and/or IgG), and this difference became nearly
significant (aRR 1.6; CI: 0.96 – 1.69).
If one looks at the 313 persons who were PCR-positive at the beginning (about half of them
got HCQ as preemptive therapy), 22.2 % of the HCQ group and 18.6 % of the control group
got PCR-confirmed symptomatic COVID-19 (aRR 0.96; CI: 0.58 – 1.58).
Altogether, 12 persons from the control arm and 11 from the HCQ arm were taken to
hospital. 8 vs. 5 died. However, there are no informations how many of them were from the
PEP vs. therapy arm.
Among PEP participants, the median time lag between exposure and assignment to HCQ or
standard care was 4 days. The RR war 0.89 if HCQ started until day 3, 0.93 if started on day
4-6 and 4.09 if started at day 7 or later. All these RRs are insignificant. Unfortunately, the
time interval up to 3 days is not divided into shorter intervals; this would have been helpful
to compare with the results of BOULWARE et al. which suggested that very early PEP on day
1 or 2 may have some protective effect, and the results of BOULWARE et al. showed a time
effect that was reminiscent of HIV PEP.
Except for the open question of the effect of very early PEP (especially on day 1), the results
from MITJA et al. destroy all hopes about HCQ PEP in a real word setting (a possible
favorable effect on day 1 would not meet the requirements of a real word PEP setting, but
would be of academic interest).

In summary, in the moment it doesn’t look very well for HCQ/CQ as a (highly?) effective
chemoprophylaxis at least for the elderly. Maybe one may need to combine it with another
agent; however, as mentioned above, only 7 trials analyze such combinations (1 x
bromhexine, 3 x zinc, partially in combination with vitamins, 1 x tenofovir/emtricitabine, 1 x
azithromycine).
No trial examines the combination of hydroxychloroquine with interferon alpha 2b
intranasal spray (2 times a day) as suggested by YANG A et al., who expect additive effects
because both agents act on two different mechanisms. There is already some good
experience with interferon alpha 2b from an old RCT where participants who used interferon
alpha 2b nasal spray and a control group without interferon were inoculated with common
human coronavirus (TURNER et al. 1986). There were less symptomatic infections in the
interferon group (41 vs. 73 %), and, more important, the mean total symptom score was
much lower (9.2 vs. 23.4) (p = 0.003).
However, the situation is even more delicate meanwhile: LI G et al. discovered in vitro large
differences in the antiviral activity against SARS-CoV-2 between both stereo-isomers of CQ
and HCQ. S-HCQ was more effective by 60 % compared to R-HCQ (in CQ, the difference was
also found, but smaller). The available CQ/HCQ drugs in therapy and trials are racemous
(50/50). So from now, any trial with HCQ would only make sense if S-HCQ is applied, but at
first, this would have to be made available on the market in large amounts.

12
Finally, ROSENKE et al. tried HCQ for prophylaxis and treatment (starting 12 hours after
inoculation) in animal models (Syrian hamsters, rhesus macaques), including very high
dosage in the Syrian hamster model. Except for some small, but significant advantages in the
total symptom score for the macaques, there was no other benefit from HCQ, e.g. with
regard to viral load or lung damage. In summary, HCQ failed in animal models of both
chemoprophylaxis and treatment.

First reports of preventive effects of chemoprophylaxis (except for HCQ – see above)
Beside the HCQ studies mentioned already above, there are so far four medium- to lowquality trials which reported favorable results about chemoprophylaxis. The fourth one is
not termed as a study or trial but just as an informational report by the authors themselves.
The first and most important one is about umifenovir (Arbidol) in PEP. The paper by ZHANG J
et al. was already published on February 26th on the ChinaXiv Server. Though it is the most
successful study with the (comparatively) (!) highest quality among the four ones mentioned
in this section, it got no recognition and reception in the western world. However, on
ChinaXiv, it was the sixth most read paper among all papers published in 2020 (judged in the
middle of May 2020; including also all papers about other subjects but COVID-19).
In their retrospective, non-randomized trial, ZHANG et al. compared the incidence of new
COVID-19 infections among exposed HCWs and household contacts of infected people who
took either Arbidol or oseltamivir for prophylaxis in a PEP setting. Compared to oseltamivir,
HCWs who took umifenovir instead of oseltamivir reduced their risk of COVID-19 infection
by 95 % (point estimate; OR: 0.049; CI: 0.003-0.727; p = 0.0276) and household contacts of
infected people by 99 % (point estimate; OR: 0.011; KI: 0.001 – 0.125; op = 0.0003).
Compared to umifenovir, intake of oseltamivir was associated with an OR of 20.446 (CI:
1.407 – 297.143; p = 0.0271). Though the trial involved only 124 HCWs and 66 members
from 27 families, the results became significant (HCWs) or even highly significant (household
contacts). The usual dose for Arbidol was 200 mg TID, and household contacts took it for 4 –
14 days (mean: 7.1 days).
In their final publication in Current Medical Science, ZHANG et al. calculated Hazard Ratios
instead of Odds Ratios. The HR for household contacts was 0.025 (CI 0.003-0.209; p =
0.0006), offering 97.5 % protection, and for HCWs the HR was 0.056 (CI: 0.005-0,662, p =
0.0221), offering 94.4 % protection.
Meanwhile, oseltamivir was found to be ineffective against COVID-19 (TAN and JIN). Thus
retrospectively, one can argue that oseltamivir was a sort of placebo. Then this trial was
“pseudo”-placebo controlled. Moreover, during the early phase of the epidemic in China,
people didn’t know what helps better against COVID-19. Both oseltamivir and umifenovir
were expected to have some preventive effect against the influenza-like disease, based on
past experiences with influenza. Therefore it is improbable that there was a systematic bias
between those who chose umifenovir and those who chose oseltamivir. They possibly
decided to take what they had already available at home, or they bought it according to their
personal preferences. This mimics a sort of randomization. In summary, with the knowledge
we have meanwhile about umifenovir and oseltamivir, one may call this trial retrospective,
“pseudo”-placebo-controlled, “pseudo”-randomized.

13
In another retrospective trial, even low doses of Arbidol (200 mg per day) and less consistent
use (6.7 days on average during the last two weeks before COVID onset) proved to be very
successful (p < 0.001) for prophylaxis in HCWs (YANG C et al.), but the effect was smaller
than in the case of ZHANG et al. where most participants took 600 mg per day (200 mg TID):
Among infected HCWs, 23.2 % had taken any Arbidol within the last two weeks before
disease onset, whereas among uninfected HCWs, this quote was 56.5 % (OR = 0.214, KI:
0.109 – 0.420, p < 0.001).
Bearing in mind that the thresholds for hospitalization are extremely low in China, 36.8 % of
the infected 19 HCWs who had taken Arbidol prophylactically (and then therapeutically, with
higher dose) were hospitalized, compared to 65.1 % (41/63) infected who had not taken
Arbidol (OR = 0.313, sign.). After age-matching, this difference lost significance, but became
a strong trend (p = 0.091), probably as a consequence of underpowering. Four of the 63
infected HCWs without Arbidol and none of the 19 infected HCWs with Arbidol prophylaxis
developed severe pneumonia. Arbidol didn’t delay viral clearance after age-matching
(duration of positive throat swab: r = - 0.240; p = 0.056).
Whereas oseltamivir is recognized meanwhile to be ineffective with any regard to COVID-19,
the effectiveness of Arbidol in the treatment of manifest infections is still open to debate.
Among six trials, one small trial showed no effect (LI Y et al.), one trial showed favorable
effects only in patients with non-severe disease (XU K et al.), and four trials showed
favorable effects (ZHU Z et al., DENG L et al., CHEN W et al., LIU Q et al.). LIU Q et al. found a
reduction in mortality of 81 % following adjustment. Taken together, these data from the
therapeutic use of Arbidol are far from any “breakthrough” which may be interesting for the
media, but the results are still more favorable than what became known about
hydroxychloroquine or lopinavir/ritonavir during the last weeks.
WANG X et al., based on their own in vitro results, concluded that umifenovir must be very
effective against COVID-19; however, the doses which were given in the therapeutic trials
might have been too small (they recommend at least 800 mg per day) and this may explain
why the clinical results were not as favorable as expected from laboratory data.
There are three registered trials about Arbidol, one large, but only observational trial with
1000 participants (ChiCTR20000295920; PEP; high-risk contacts and HCWs), one small
randomized trial which compares HCQ and Arbidol (CHICTR2000029803; PEP, 320
participants, close contacts) and a non-randomized trial with 500 HCWs with Arbidol in
combination with Jinyebaidu granules (CHICTR2000029728). Thus all three trials have
serious limitations (two are not randomized and the randomized one is rather small), and
since all three trials are from China, it is doubtful whether they can be completed
successfully.
The second chemoprophylaxis trial is about interferon α nose drops and Thymosin-α1. It is
registered in the WHO registry and the first of the 88 registered trials which is already
published (MENG Z et al.). 2944 HCWs from a hospital in Hubei province applied interferon α
Type 1b nose drops four times a day (2-3 drops/hole). Among them, 529 HCWs were
exposed to high COVID risks (isolation wards, fever clinics), and they got weekly injections
(s.c.) of 1.6 mg thymosin-α1 alongside of interferon nose drops. The other HCWs were of low

14
risk of exposure to COVID-19. At the end of the trial (28 days), none of them had acquired
confirmed or presumed COVID infection or any other respiratory infection. However, there
was no control group. Furthermore, the authors didn’t estimate or model how many
infections would have to be expected without that intervention, based on experiences from
other hospitals in this epidemic region und during that time frame. This makes it very
difficult to evaluate the effect of this intervention.
It would be interesting to confirm these results in a randomized trial; however, there is no
trial of that kind registered by the WHO registry. There is only one trial about interferon α 1b
spray in HCWs (without thymosin) (CHICTR2000030013). Since it is from China too, it is
doubtful whether it can be completed.

Finally, LEE et al. reported from a long-term care facility from South Korea where two
employees were found to be infected: a social worker who worked some time in spite of her
symptoms before COVID diagnosis, and a caregiver who possibly got her infection on a
different pathway since she had no close or relevant contact to the infected social worker.
189 inhabitants of the long-term care facility (mean age: 80 years) and 22 staff members
took 400 mg HCQ a day (without a loading dose because there were many small people
there, many of them about 40 kg). Within the next two weeks, there were no new infections
among the 211 people who got HCQ. Again, there was no control group, and both infected
women worked usually with face masks, but it is not sure whether they wore them all of the
time at work. So maybe the inhabitants and the other staff were protected solely because of
the face masks, therefore it is hard to guess whether (and how many) infections would have
occurred in the absence of HCQ PEP. The authors point to these limitations and that’s why
they regard their paper only as a sort of communication and not as a trial.
In summary, in direct comparison to the Arbidol trials from ZHANG et al. and YANG et al., the
evidence from MENG et al. and LEE et al. has to be judged as much weaker because of the
missing control group. Arbidol outcompetes both other trials. However, due to the
uncertainties and low to medium quality of either trial, it could also be suggested to
combine Arbidol tablets with the strategy of local prevention (interferon nose drops) and
immunostimulation (thymosin α 1).
Independent of the drugs used, this combination of (1) an antiviral, (2) a local preventive
agent for the upper respiratory tract and (3) an immunomodulatory or –stimulating agent
may be helpful in a preventive setting.
But since umifenovir is not approved by the FDA and the EU, the future of further trials on
Arbidol for chemoprophylaxis looks extremely bad. It is probably impossible to complete the
three ongoing trials in China due to the lack of infections, and if they can be completed some
day, they will again be of lesser quality for the reasons mentioned above, so it is improbable
that they will be acknowledged then. Russia didn’t start any registered trial about Arbidol. It
looks as if the chance of the most promising agent of chemoprophylaxis (at the moment) will
be missed definitely and forever.

15
Other candidates for chemoprophylaxis (not studied in the 88 registered trials)
A longer list of possible candidates for chemoprophylaxis is presented on pages 37 – 47 in
this german language paper (http://freepdfhosting.com/bedd8b1c79.pdf). Some of these
candidates are therapeutic drugs which are already used in trials for the treatment of
COVID-19 like favipiravir, so why shouldn’t they be considered with regard to
chemoprophylaxis as long as such critical drugs like CQ, HCQ or lopinavir/ritonavir are?
Other possible candidates are phytochemicals which are supposed to be effective against
COVID-19 only because of in silico or in vitro evidence or as part of TCM experience. They
may have fewer side effects and may be tolerated better than chemical drugs. If their
preventive effects are less strong, they may be better suited for combinations, with some
similarities to many herbal TCM drugs which are also combinations of products from many
different plants.

Mentioned in the german paper are also:
● Acetic acid disinfection (as simple homemade inhalation based on common vinegar) (see
PIANTA L et al.; suggested for early therapy, but may also be helpful in a PEP situation to
reduce local viral load in the respiratory tract following possible exposure)
● Acidified sodium chlorite solution (see KARNIK-HENRY MS; nasal spray and oropharyngeal
gargle as PREP or immediate PEP in HCWs, up to 4 times a day/work shift)
● alpha-1-antitrypsin for inhalation (TMPRSS2 inhibitor) (AZOUZ MP et al.)
● Alpha-lipoic acid (ZHONG M et al.) (adjuvant to other drugs)
● Baicalin, Baicalein (LIU H et al., SU H et al.)
?● Bromhexine (alone, without HCQ; an effective TMPRSS2 inhibitor) (see HABTEMARIAM et
al., DEPFENHART et al., MAGGIO and CORSINI for prophylactic and therapeutic options)
Bromhexidine was another candidate that was associated with some hopes; however,
clinical data aren’t available so far and in vitro experiments from HÖRNICH et al. warn to be
careful: in cell culture, bromhexidine acted paradoxically. Though bromhexine is an inhibitor
of TMPRSS2 like camostat, it activated the fusion of infected and uninfected cells to promote
transfection and may thus contribute to infection, in contrast to camostat. Because of this
effect, use of bromhexine in prophylaxis or therapy may possibly increase SARS-CoV-2
related risks.

● COX-2-inhibitors (e.g. Celecoxib) (adjuvant?) (HONG W et al., cf. HUH K et al.)
● Curcumine + piperine (see SHETTY et al. (2), ZAHEDIPOUR et al. and GUPTA et al.), also in
combination with zinc (see ROY et al. for the purpose of prophylaxis and therapy since
curcumine is able to dampen cytokine storms)
● Doxycycline (→ see below)

16

● Griffithsin (MILLET J et al. with experience in association with MERS coronavirus)
● Indomethacin (MARINELLA et al.)
● Influenza immunization? (see ZANETTINI et al.) (country-level data on influenza vaccine
coverage of elderly and COVID mortality suggest a reduction of mortality by 28 % if vaccine
coverage increases by 10 %. However, there is a need for further investigations based on
individual data). The same applies to the elder population in Italy (> 65 years) where a strong
negative correlation was found between the regional influenza vaccination uptake rate (> 65
years) and COVID mortality. There were three different vaccines available in Italy for that
influenza season. Live attenuated influenza vaccine would be more likely to lead to local
trained immunity than inactivated vaccine. Social bias may also explain the vaccine effect,
since higher economic status may be associated with higher vaccine uptake and better
general health (less comorbidities), thus reduced risks of COVID mortality (MARINHERNANDEZ et al.).
In Brazil, recent vaccination with inactivated trivalent influenza vaccine reduced mortality by
17 %, mechanical ventilation by 18 % and risk of ICU care by 8 % among 92.664 patients with
proven COVID-19 infection (FINK et al.)

● Inhibitors of feline coronavirus (VUONG W et al.)
● Interferon lambda (ANDREAKOS and TSIODRAS)
● Interferon alpha 2b as partner for combination with other agents (e.g low-dose HCQ; see:
YANG A et al.; see also TURNER et al. for use in common human coronavirus)
● iota-Carrageenan (→ see below)
● Ivermectin (CALY L et al., BRAY M et al.; PATRI and FABBROCINI).
● Heparin (unfractionated heparin) or enoxaparin (TANDON R et al.)
● Hesperidin (HAGGAG et al.), a promising natural herbal agent which “interferes with viral
entry through ACE2 receptors, improves the host cellular immunity, minimizes the release of
inflammatory mediators and its mixture protects against venous thromboembolism.”
(HAGGAG et al.). They suggest hesperidin for prophylaxis and treatment and plan a clinical
trial.
● Lactoferrin (CARVALHO et al.)
● Nafamostat (YAMAMOTO et al., KO M et al., HOFFMANN M et al.) (SARS-CoV-2 inhibition
much stronger than remdesivir and 15 times stronger than camostat)
● Naproxen (TERRIER O et al.)
● Niclosamide (GASSEN NC et al.)

17

● Nicotine substitution (nicotine patch etc.) (FARSALINOS K, see also NORDEN et al.) (antiinflammatory)
● oral polio vaccine (OPV) (see CHUMAKOV et al. for details) to enhance innate immunity
against viruses, probably mediated by interferons, in the same way like BCG vaccine.
However, compared to BCG, OPV has many advantages: side effects are much rarer, it is
easy to administer, cheap, and can be produced in large amounts in a short time. Moreover,
if the protective effects disappears with time, OPV vaccination can be repeated with other
sorts of OPV vaccines since there are three different monovalent vaccines (against three
different types of poliovirus) available, of which vaccine against type 2 is the most
problematic with regard to (rare) complications and should be avoided.
Under such protection, one could gain more time to develop a very safe and very effective
COVID-19 vaccine. However, there are serious concerns that such a strategy might hamper
the strategy of polio eradication because it would be inevitably associated with some degree
of release of polio viruses into the population and environment. Even if the viruses from the
vaccine are attenuated and non-pathogenic, they may mutate back to become more
pathogenic. Thus, this strategy would counteract the WHO strategy to stop OPV vaccination
worldwide in favor of IPV vaccination. As an alternative, one might consider measles vaccine
(see: American Society for Microbiology and NETEA et al.).
● Phytochemicals like Resveratrol (see also MARINELLA et al.), Luteolin, Myricetin, Apigenin,
Quercetin, Kaempherol, Baicalin, Wogonosid (MCKEE et al.) or indian traditional herbal
medicine (DIVYA M et al.),
Quercetin is suggested to be combined with vitamin C, and also dosage was recommended
(for prophylaxis and mild disease, 250 – 500 mg quercetin BID and 500 mg vitamin C BID)
(COLUNGA BIANTACELLI et al.). However, since quercetin stimulates T-helper cells to
produce interferon gamma, which acts proinflammatory, one may ask whether quercetin is
suited for treatment, in spite of its antiviral activity.

● PUFAs for lowering cholesterol (PUFAs = polyunsaturated fatty acids; adjuvant) (WANG H
et al., see also DE SPIEGEELER et al. and MEHRA et al. for the protective effects of statins
which may indicate some protective effect of PUFAs by cholesterol lowering)

● Remdesivir inhalation/nebulisation (for PEP) (see SUN D) (nebulisation of lyophilized
remdesivir powder; however, for simple use at home, it would be better to develop dry
powder)

● Silibinine/Silymarine (URBANI et al.) (multi-target activity against SARS-CoV-2, but also
liver protection with regard to the side effects of some drugs used against COVID like rising
levels of transaminases or biochemical hepatitis)

18
● Spermidine (GASSEN NC et al.; problem: bioavailability, see SHMOLLICH H)

● Trehalose (as eye drops) for local PREP/PEP of the eye (in case of contamination risks of
the eye) (SHETTY et al. (2)). Because of receptors like ACE2, different parts of the eye (e.g.
cornea, conjunctiva) are susceptible for COVID-19. The nasolacrimal duct may enable that
local infection of the eye area to enter the respiratory tract where it can expand.

● Vitamin D (1000 IU/d), magnesium (150 mg/d), vitamin B12 (0.5 mg/d) (for PEP and early
therapy, see TAN CW et al. who were able to show in a small cohort trial that this
combination significantly reduced the risk for the need of oxygen support or ICU).

However, with all these uncertainties and disappointments so far, it seems to be wise to
study new candidates for chemoprophylaxis at first in animal models like rhesus macaques,
before starting long-lasting and costly clinical trials. Rhesus macaques show the same agedependent effects of the disease like humans (YU P et al.), so it is important to select middleand old-aged individuals for such tests. In fact, WILLIAMSON et al. demonstrated that rhesus
macaques developed no clinical disease or only very mild disease with low viral load, when
they were treated with Remdesivir and when they got the first dose of Remdesivir 12 hours
after challenge with a high dose of SARS-COV-2. Remdesivir was extremely effective in this
setting of very early treatment, which would never be reproducible in clinical reality since no
infected person will be diagnosed and symptomatic 12 hours after exposure. So, under real
life conditions, this experiment mimics PEP (instead of early therapy).
Of course Remdesivir i.v. is maximally inappropriate for PEP (e.g. because it has to be
administered by infusion), but this experiment of WILLIAMSON et al. is a proof of principle
that PEP works, and that rhesus macaques models are suited to study the effects of different
candidates for their effects on PEP. Such experiments may offer results within a few weeks
and allow quick decisions which candidates may work in chemoprophylaxis and which
candidates don’t deserve further consideration for this purpose.
That said, only three of the candidates will be discussed here.
First, YATES et al. suggested doxycycline at low dose (20 mg BID instead of the usual
therapeutic dose of 100 mg BID) for PREP in HCWs and published a design for a DOXYPRO
trial. They mentioned a lot of different reasons why doxycycline is expected to be effective
against COVID-19 and in prophylaxis, e.g. its antiviral and anti-inflammatory properties and
its efficacy against Dengue and Chikungunya infections, the inhibition of metalloproteinases,
papain-like proteinase and possibly 3C-like main protease, among other effects. Since
doxycycline acts as an ionophore (like CQ/HCQ), it can be interesting to combine low dose
doxycycline PREP/PEP with zinc supplementation. YATES et al. suppose that many
participants will already be used to take supplements including zinc, and should continue to
do so in a prescribed manner. Doxycycline may help to increase zinc concentration inside the
cells, where zinc inhibits virus replication.

19
There is so far very little experience with doxycycline in COVID-19 except for a few
theoretical papers in favor of doxycycline. AHMAD I et al. reported about the treatment of
54 COVID-19-infected patients in three long-term care facilities in New York (median age 67
years, many comorbidities, 91 % hypertension, 39 % diabetes; 31 % needed ventilation).
They got HCQ and doxycycline (100 mg BID). 46 patients recovered, 11 % (6) had to be
transferred to hospital, and 6 % (3) died. Compared to experiences from another long-term
care facility (57 % transfer to hospital, 22 % dead) as a sort of “control”, these results are
fairly favorable. 93 % of the patients had no side effects and only one patient had to
interrupt because of seizure. RISCH reported of as yet unpublished data that meanwhile
about 200 patients from these long-term care facilities were treated that way, and only 9 of
them (4.5 %) died.
Maybe there is a special synergism between HCQ and doxycycline; otherwise, with the null
or possibly deleterious effects of HCQ in COVID-19 in mind, the favorable effect of this
combination would have to be solely attributed to doxycycline. A supplementation of zinc
was not part of this trial, but would be an interesting adjuvant in the presence of two
ionophores at the same time.
Moreover, SZOLNOKY suggested the combination of doxycycline and vitamin C not only for
treatment, but also for prophylaxis.
Based on experiences with cancer cells (coadministration of vitamin C and doxycycline
resulted in robust eradication of cancer stem cells In vitro by blocking mitochondrinal
protein translation and ATP production from glycolysis), SZOLNOKY expects that doxycycline
with the amplifier vitamin C will result in mitochondrinal damage of virally compromised
cells and the attenuation of immune response by the inhibition of glycolysis in proinflammatory immune cells. SARS-CoV-2 is suggested to prefer chronologically aged and
senescent lung cells for binding and replication which results in stormy inflammation and
subsequent fibrosis. Senolytic drugs like doxycycline could prevent postinflammatory fibrotic
transformation.
Since very low concentrations of doxycycline block mitochondria and act in an antiinflammatory way, a prolonged course of low-dose doxycycline (like for the treatment of
rosacea) together with vitamin C is suggested as “an inexpensive, safe and promising
approach in antiviral prophylaxis and treatment.”
In Germany, doxycycline is recommended for systemic treatment of rosacea in a dose of 40
mg/day in a partially retarded galenic formulation (Oraycea, Galderma), releasing 30 mg
directly and 10 mg in a retarded manner.

Second, in a SARS-CoV-2-equivalent pseudovirus model, unfractionated heparin (UFH) and
enoxaparin (as well as some other sulfated polysaccharides, e.g. from algae) effectively
inhibited viral entry into mammalian cells. Whereas systemic UFH/enoxaparin has dangerous
side effects and may interfere with anticoagulant therapies, they are very poorly resorbed
even following inhalation of high doses; inhalation resulted in very poor serum
bioavailability. Since the nasal epithelium is probably the major portal of viral entry and
initial infections and also the dominant source for transmission to other people, TANDON et

20
al. suggest “that a self-administered nasal spray of UFH may be a simple, safe and effective
prophylactic to lower the rates of SARS-CoV-2 transmission”. They report that toxicology and
pharmacokinetic studies about long term use are currently underway. Single use was already
shown to have no toxicity and very poor serum bioavailability.

Finally, carrageenan has not been tested so far with regard to SARS-CoV-2. In 2006,
carrageenan, and at most iota-carrageenan, was found to be effective against many viruses,
including the very resistant HPV virus which is hard to inactivate by usual antiseptics and
disinfectants (BUCK et al.). Meanwhile, carrageenan is used in some formulations (e.g.,
sliding gels) against HPV.
In 2014, KOENIGHOFER et al. demonstrated in two randomized double blind placebo
controlled trials that iota-carrageenan nasal spray had significant effects in acute common
cold. It shortened the duration of the disease, the number of relapses and accelerated virus
clearance. 46 % of the patients in that study suffered from human rhinovirus, 25 % from
human coronavirus, and 14 % from influenza A virus. Most important, the effects of iota
carrageenan were much more pronounced in coronavirus infections than in other infections.
So there are good reasons to test iota carrageenan against SARS-CoV-2 in vitro. If it is
effective, it would be an interesting candidate for local prophylaxis as nasal spray or nasal
douche and gargle in a similar way as is suggested for Povidone-iodine which is already
subject of a non-randomized clinical trial with HCWs (NCT04364802) as a sort of local
PREP/PEP. They have to use the nose spray and gargle before, in the middle and at the end
of their work shift. 15 seconds of contact were enough to inactivate SARS-CoV-2 completely
in concentrations as low as 0.5 % in vitro (BIDRA et al. for the purpose of oral rinse).
LIANG B et al. suggested that local application of povidone-iodine may reduce the viral load
in the nasal tract in infected people. This will not only reduce their infectivity with regard to
other persons, but also their own infectivity with regard to the expansion of their infection
towards lower parts of the respiratory tract. The idea is to keep the infection confined to the
upper respiratory tract and to avoid its spread in the direction of the lungs. Therefore, local
povidone-iodine is not only recommended for prophylaxis but also for infected people early
in the course of their disease in the hope that it would reduce viral load and the risk of
descent of the infection in the respiratory tract.
However, if iota-carrageenan is found to be as effective as povidone-iodine against SARSCoV-2, it has some advantages. First, it is very well tolerated (used in food, even for babies)
and there are no concerns about doses and side effects. Second, there are no concerns
about discoloration of clothes or other objects which may be associated with the use of
povidone-iodine as spray, gargle or nasal douche. Third, carrageenan has a very good
adherence (and thus retention) on the top of the mucous membrane, resulting in a depot
effect and long lasting protection by a thin gelatinous layer.
Finally, it was already shown that iota and kappa carrageenan in saline irrigation solutions
are safe and non toxic and have no detrimental effects on epithelial barrier structure and
ciliary beat frequency. Moreover, kappa carrageenan increased the transepithelial electrical
resistance and suppressed IL-6 secretion (RAMEZANPOUR et al.). There are already nasal

21
sprays available with both iota and kappa carrageenan – a combination which seems to
make sense.
However, bottles with 20 ml of nose spray (which are already available on the market) are
too small and too expensive if one wants to use them for PREP/PEP or in the early
therapeutic setting mentioned above. For purpose of gargle or nasal douche, one needs
much larger amounts of iota carrageenan solution. Povidone-iodine solution for spray or
gargle has to be prepared by diluting the original solution of for example 10 % PVPI by 1 : 30.
With regard to iota-carrageenan, one should consider to provide it as a powder which has to
be dissolved in physiological salt solution before use as gargle or nasal douche. Of course it
has to be tested whether this simple method works and doesn’t impair the antiviral activity
of carrageenan. If it works, it would be a simple, cheap (and “clean”) method not only for
nasal spray, but also for nasal douche and gargle. It is probably the combination of all three
modes of application (spray, douche, gargle) which may be most effective to reduce the viral
load in a preventive setting as well as in the case of early therapy of infected people.
In Argentinia, a small observatonial trial (70 participants) for COVID prevention by local
application of iota-carrageenan in the nose and Ivermectin (Ivercass 0.6 %) on the oral
mucosae (5 times a day) was registered on June 11th (IVERCAR, NCT04425850).

Summary, Conclusions
The need for chemoprophylaxis of COVID-19 infections, either to avoid infections at all or to
avoid severe disease, became even more pressing during the last weeks than it was before.
There are 88 ongoing or completed registered clinical trials of PREP/PEP as of May 13th.
However, most of these trials (and all very large ones) are confined to (hydroxy)chloroquine
alone (without any combination partner). This is very risky if HCQ/CQ fails in PREP/PEP or if it
shows only minor or moderate effects, since there are no alternatives which are examined
as well that they can be recommended for clinical use. Beside of BCG immunization, all other
alternatives are tested only in one or two clinical trials, many of them small and some
without randomization. The risk that HCQ/CQ may fail or may only offer little protection
became much higher during the last weeks because of (1) the disappointing (and in part
alarming) results for hydroxychloroquine in the treatment of COVID-19, (2) the missing
protection in people who took HCQ for other reasons like autoimmune disease, and (3) the
fact that there were no announcements of preliminary or interim results as “breakthroughs”
in the protection of health care workers.
Among the other candidates which are tested in one or two trials, many have only limited
perspectives and can, at best, offer a little protection (e.g. measles vaccination, vitamins,
melatonin), others are antiparasitic drugs which are not approved in many countries, or are
problematic because of serious side effects (like mefloquine). The hope for very good
PREP/PEP effects of HIV drugs, based on in vitro data (e.g. JOCKUSCH et al.), very good
experience with lopinavir/ritonavir for PEP in a hospital with highly exposed HCWs to MERS
without adequate protection (PARK et al.) and a report from Thailand (ZHU F et al.), are also
much smaller now since it became evident that HIV-infected people who take these drugs

22
for treatment of their HIV infection, can also get infected and seriously ill with COVID-19.
This applies to reverse transcriptase inhibitors like Tenofovir/Emtricitabine (GUO W et al.,
HÄRTER et al., KARMEN-TUOHY et al., VIZCARRA et al.), but also to protease inhibitors like
Lopinavir/Ritonavir (HÄRTER et al., KARMEN-TUOHY et al.) or Darunavir (VIZCARRA et al.).
However, in an animal experiment (ferrets) with early therapy (starting 1 day after virus
inoculation), Tenofovir/Emtricitabine was evidently superior to lopinavir/ritonavir (L/R),
which was only a little superior to HCQ, and both L/R and HCQ were of comparatively small
effect compared to placebo, whereas Tenofovir/Emtricitabine was most successful (PARK SJ
et al.).
Finally, contrary to former reports from other countries, DEL AMO et al. showed in a large
cohort study from Spain (encompassing about 75% of all HIV-infected people in Spain who
receive ART), that tenofovir as disoproxil fumarate (TDF) combined with emtricitabine, but
not (!) tenofovir alafenamide (TAF), was superior to reduce COVID-related risks. Whereas the
standardized risks of COVID infection, hospitalization, ICU care and death among all HIVinfected people under ART (standardized to age and sex of the general population in Spain
between 20 and 79 years) were 30, 17.8, 2.5 and 3.7 per 10.000 until April 15th, the risks for
people taking TDF/Emtricitabine were 16.9, 10.5, 0 and 0 per 10.000. Because only
symptomatic people got COVID tests in that time interval in Spain, COVID incidence is
essentially identical to incidence of symptomatic disease. The results are based on 12.395
HIV-infected people who took TDF/Emtricitabine (21 infections, 13 hospitalisations, no ICU,
no death) (among 77.590 who took any form of ART). In contrast, the combination
TAF/Emtricitabine (n = 25.570) resulted in 100 infections, 52 hospitalisations, 7 ICU cases
and 10 deaths (DEL AMO et al.). With this large study, the question of HIV treatments for
PREP is opened again; however, it is evident that TDF/Emtricitabine offers no full protection,
and much larger datasets are necessary to find out whether this combination is really able to
avoid ICU admittance and death.
However, in the German study (HÄRTER et al.), there were 2 seriously and 6 critically ill cases
(including 3 deaths) among 33 HIV-infected people under HAART who acquired COVID-19.
One of the serious cases and two among the 6 critical cases were treated with a regimen
including TDF/Emtricitabine (one of them died; 59 years, hypertonia, COPD, diabetes
mellitus type 2). Thus, TDF offers no full protection against critical or fatal disease.
In South Africa, HIV infection was associated with an increased risk of death compared to all
COVID infected people (aHR 1.70; p < 0.001) and among all hospitalized COVID-19 cases (aHR
1.45; p = 0.002), and death was associated with CD4 cell number < 200. However, compared
to HIV infected people who took abacavir, zidovudine or efavirenz (aHR defined as 1.00),
those who took tenofovir had an adjusted HR of death of 0.42 (CI: 0.22 – 0.78) (p = 0.006),
those who took lopinavir of 0.89 (CI: 0.36 – 2.16, p = 0.79). Azanavir (aHR 0.36) and
doletugravir (aHR 0.59) also showed favorable results comparable to tenofovir, but far from
statistical significance (DAVIES MA et al.). The results may be influenced because tenofovir is
the first-line therapy in South Africa; however, since the results rely on prescriptions and not
on actual intake of ART, the protective effect may be higher in those who take their ART
exactly as prescribed.
Since this study was about mortality, there is no information about the influence of different
ART regimes on the risk of COVID diagnosis. It is stated that 16 % of the people in that area

23
are HIV positive. The standardized mortality ratio (SMR) for COVID-19 in HIV-infected people
was 2.39 (CI: 1.96 – 2.86) compared to people without HIV. So even if the HR of dying is only
0.42 in HIV infected people taking tenofovir, their COVID incidence would then be similar to
the incidence in people without HIV, estimated on the base of SMR or aHR for death. At
least, the results of DAVIES et al. are incompatible with the hypothesis of a much lower
COVID incidence in people taking tenofovir compared to uninfected people.

Under these circumstances, there is an urgent need to extend PREP/PEP trials to other
candidate agents. Meanwhile, animal models like rhesus macaques proved to be well suited
for the simulation of PREP or PEP settings if one takes into account the age of the individuals
(YU P et al.). Instead of costly and long-lasting trials based on speculations or in silico or in
vitro data, it seems wise to test drugs or phytochemicals for PREP/PEP in the rhesus
macaque model, and results will be available within a few weeks. This offers the opportunity
to select the most promising candidates (or combinations of them) in a preclinical setting
and to avoid disappointing clinical trials.
Based on preclinical data and with the option to test them at first in a primate model, there
are many drugs and phytochemicals which are still untested with regard to a possible
efficacy in PREP/PEP. Among them, there are therapeutics like nafamostat or favipiravir, but
also doxycycline (in combination with zinc) or possibly iota-carrageenan for local prophylaxis
of the uppermost respiratory tract.
Moreover, even if HCQ/CQ alone fails, combinations of HCQ and doxycycline, zinc,
doxycycline + zinc or other drugs may still be successful. In a certain parallel to herbal TCM,
combinations of phytochemicals may also be interesting. Because of nearly unlimited
possibilities of combinations among them, animal models will be needed to quickly optimize
efficacy of such combinations. There is also slowly increasing evidence that the treatment of
COVID-19 (if necessary – mild cases without comorbidities usually don’t need treatment)
may require a combination of drugs (e.g., HUNG et al.). The same may apply to
chemoprophylaxis.
Unfortunately, the only drug which proved to be very successful in PEP so far in two trials,
umifenovir, is despised in western medicine. The point estimates of the protective effects
were between 95 and 99 % and the results were significant and highly significant. However,
no one seems to be interested in that except for China, where three additional trials about
Arbidol in PREP/PEP were registered. But it has to be expected that all of them have to be
closed due to the lack of COVID-19 patients and therefore people under exposure risks who
are accessible for PREP/PEP. Moreover, one cannot exclude the possibility that selfmedication for PREP/PEP with OTC-available drugs like umifenovir and TCM, or a
combination of both, contributed to the decrease of COVID-19 in China after people had
understood how to deal with COVID-19 and how to prevent it. As ZHANG et al. showed in
their retrospective arbidol-oseltamivir trial, already in the early phase of local epidemic,
when no one knew what may help against COVID-19, people with enhanced risk of infection
(like exposed HCWs or household contacts) acted on their own responsibility and started to
take drugs of which they thought that they can help to prevent infection or to improve the
course of the disease in case they get it. If such a behavior was already established in China
in the early phase of the epidemic, it is probable that engagements in PREP/PEP (including
herbal TCM) may have increased over time with increasing knowledge and understanding

24
about the severity and risks of that disease which is not simply “another influenza”. It is
reported that more than 85% of infected people used TCM (DU et al.). Thus, self-medication
for prophylaxis and early treatment (which may reduce viral load and infectivity) may be part
of the Chinese success story, and umifenovir was shown to be a part of it. This makes it hard
to understand why western medicine, completely fixed on hydroxychloroquine, ignores
umifenovir and doesn’t start trials on its own, beginning with a rhesus macaque model.
There is no time to wait for results from China which probably will never come.
Anyway, effective chemoprophylaxis MUST be possible. There is no doubt that it works since
WILLIAMSON et al. proved it in a rhesus macaque model, using Remdesivir in a PEP setting.
Of course Remdesivir is not suited for PREP or PEP (at least as long as it isn’t available for
inhalation), but even if one ignores the Arbidol trials, the WILLIAMSON trial definitely proved
that PEP (and, as a consequence, also PREP) does work. It’s a proof of principle.
There are also other proofs of principle. There are therapeutic drugs for special diseases
which were found to be associated with a reduced risk of COVID infection and/or severe
disease. Examples are DPP-4-inhibitors in diabetic people (RHEE et al; aOR for death or ICU:
aOR: 0.362; CI: 0.135 – 0.971 compared to diabetic people without that drug), or
antiandrogenic therapies with 5α-reductase inhibitors (DUGA et al.). None of these drugs
protected the patients by nearly 100 %, and these drugs don’t seem to be suited to give
them to people without the underlying disease solely for the purpose of COVID prevention.
However, these drugs are another proof of principle that chemoprophylaxis actually works,
at least as partial or moderate protection.
Since nobody can accept daily infusions of remdesivir for PREP or PEP, and nobody will
accept the enormous costs for that, it is now the urgent task to step down from the high
level of remdesivir and to find out what drug or phytochemical, or what combination of
drugs and/or phytochemicals, is also highly effective in PREP/PEP, but easy to access (at
best, OTC), cheap and safe.
A large multicenter trial for chemoprophylaxis with the aim to get results quite quickly and
without hydroxychloroquine could possibly look like this:
● one arm Arbidol (200 mg TID)
● one arm interferon α 1b nose drops or spray and weekly Thymosin α1 injection (s.c.) (like
MENG Z et al.)
● one arm doxycycline (100 mg BID) + zinc (usual dose of doxycycline in a PEP setting, in
contrast to smaller dose in a PREP setting as suggested by DOXYPRO) (YATES et al.)
● one arm local prophylaxis by povidone-iodine (nasal spray, gargle, maybe nasal douche)
(several times per day, depending on the sort and occurrence of exposure)
● one arm local prophylaxis with iota-Carrageen powder diluted in physiological salt solution
as nasal spray or nasal douche and gargle (several times per day, depending on the sort and
occurrence of exposure)
● one arm without any intervention

25
Results of such a trial would allow to combine one drug for systemic prophylaxis with
another drug for local prophylaxis, maybe also adding an immunostimulant like thymosin α if
still necessary, depending on the degree of protection that each single method offers taken
alone.
Moreover, if hydroxychloroquine shows a small or moderate protective effect in the ongoing
trials of “HCQ alone”, one may still consider its combination with doxycycline as far as
systemic prophylaxis is concerned. Again, this doesn’t exclude the additional utilization of
local prophylaxis. In the absence of a highly effective systemic protection, the combination
of systemic and local methods may become very important. This makes it so important to
find out more about iota-carrageenan, since the use of carrageenan in local prophylaxis is
much simpler than povidone-iodine.
Moreover, it is even possible to combine three principles for PEP (and also for early therapy):
● local prophylaxis inside the nasopharyngeal tract (with the intention of an antiseptic
effect), e.g. povidone-iodine or (if effective) iota-carrageenan as spray, nasal douche and
gargle,*
● local prophylaxis of upper, but also more proximal (lower) parts of the respiratory tract
(lower than the oropharynx) by inhalation (e.g., acetic acid, nebulized remdesivir powder,
interferon inhalation, NO, NORS, PUL-042).
● systemic prophylaxis e.g. by antivirals like umifenovir or any of the other agents
mentioned above which would have to be taken per os.

Provided that iota-carrageenan really works against SARS-CoV-2, one can even develop and
study a sort of “local peri-exposure prophylaxis”, independent of some sort of systemic
prophylaxis beside of that, for situations when a predictable risk of exposure is expected for
any reason and cannot be avoided:
● pre-exposure: nasal spray or nasal douche and gargle with iota-carrageenan powder
diluted in water or physiological salt solution in order to generate a thin layer of carrageenan
on the top of the epithelium of the nose and nasopharynx as a sort of chemical and physical
barrier to protect the epithelium
● directly after exposure risk: povidone-iodine (about 1 % PVP-I) as nasal spray or nasal
douche and gargle (this may kill and wash out viral particles from the top of the carrageenan
layer)
● some time later the acetic acid procedure (inhalation) described by PIANTA et al.
Of course the whole procedure is time consuming and not for daily routine life. However, it
may be interesting for people with enhanced risks (age, comorbidities) who have to expose
themselves to infection risks which they cannot avoid (e.g., a meeting with many people for
professional reasons). Steps 2 and 3 may also be relevant for longer lasting PEP and early
treatment after PCR diagnosis or first symptoms (even without PCR diagnosis) for the

26
reasons described by LIANG et al., i.e. reducing viral load and inhibiting the expansion of the
infection from the uppermost respiratory tract more downwards.
____________
* some other options for future nasal sprays against COVID-19 are described in the PCCA blog:
https://www.pccarx.com/Blog/coronavirus-update-hand-washing-nasal-sprays-and-masks-whatresearch-is-saying

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