Nara Medical University have developed candies from tannins of persimmon as antivirals against the SARS-CoV-2 virus


A Japanese study team compromising of researchers from Nara Medical University, National Hospital Organization Nara and Kio University have developed candies from tannins of persimmon as antivirals against the SARS-CoV-2 virus.

In a previous study, the same research team showed that tannins from persimmon also exhibited antiviral effects against non-variant and alpha variant. The murine study findings also suggested that oral administration of persimmon-derived tannin may help reduce the severity of SARS-CoV-2 infection and transmission of the virus.

The study findings were published on a preprint server and are currently being peer reviewed.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains a serious, global threat. The transmission of this virus from patients with no or mild symptoms by means of dispersed saliva poses one of the greatest challenges to ending the ongoing multi-year pandemic [1,2].

A persimmon (Diospyros kaki) is an edible fruit that contains a large amount of persimmon tannin.

Because of its large molecular size, persimmon-derived tannin has strong antioxidant, immunomodulatory, antimicrobial, and antiviral activities against various viruses [3–6]. We have previously shown that persimmon-derived tannin inactivates SARS-CoV-2 in vitro and that administering persimmon tannin into the oral cavity of a hamster model reduced the severity and transmission of SARS-CoV-2 infection [7].

Persimmon-derived tannin may be a valuable candidate substance to use for COVID-19 protection and medical therapy.

In 2021, the delta variant of SARS-CoV-2 (B.1.617.2) became the predominant strain of SARS-CoV-2 in Japan, particularly in August. The delta variant was first identified in England in March, 2021, and it rapidly spread around the world.

The delta variant is highly contagious, and several large studies have shown that the delta variant causes more severe disease compared with the other identified SARS-CoV-2 variants, including the alpha and omicron variants [8–11]. A study in Canada reported that the delta variant caused more than twice the amounts of hospital admission, ICU admission, and death compared with the alpha variant [8].

Additionally, another study in England [10] revealed that the risk of hospital admission and death in patients infected with the delta variant was more than double that of patients infected with the omicron variant.

Salivary glands are important sites for the replication of SARS-CoV-2; therefore, the inactivation of virus in the saliva may inhibit droplet and aerosol transmission of SARS-CoV-2 [2].

In this study, we evaluated the antiviral effects of persimmon-derived tannin against the delta variant of SARS-CoV-2 in human saliva. Herein, we used tannin-containing hard candy to deliver and retain persimmon-derived tannin in the oral cavity. Healthy volunteers and patients with COVID-19 were instructed to eat this candy and then salivate.

Persimmon-derived tannin inactivates the delta variant of SARS-CoV-2 in vitro

First, to investigate the antiviral activity of persimmon-derived tannin against the delta variant of SARS-CoV-2 in vitro, we examined the replicative ability of the delta variant reacting with persimmon-derived tannin. The results show that the persimmon-derived tannin inactivated the virus in a concentration- and exposure time- dependent manner (Fig. 1). These data are consistent with our previous report in which we demonstrated the antiviral activity of persimmon-derived tannin against non-variant and alpha variant SARS-CoV-2 [7].

Saliva sampled while eating persimmon-derived tannin-containing candy inactivates the delta variant of SARS-CoV-2 in vitro
Next, we investigated the antiviral effects of saliva collected from three healthy volunteers before or after sucking on a persimmon-derived tannin-containing hard candy for 10 min. Hard candy is a good system for spreading tannins in the oral cavity. The antiviral effects of saliva from each volunteer are shown in Figure 2. Saliva collected either before or after eating the control candy did not suppress the virus, whereas saliva collected after eating the persimmon-derived tannin-containing candy significantly suppressed the virus titers by approximately 1/1000.

Administering persimmon-derived tannin-containing candy to patients with COVID-19 caused by SARS-CoV-2 delta variant can suppress the viral load in their saliva We then conducted a clinical examination using the same tannin-containing hard candy. Three patients with COVID-19 and mild symptoms, who had no major underlying disorders, were administered the candy, and their saliva was sampled (Fig. 3).

RNA was extracted from each sample, and qPCR was performed to detect the nucleocapsid gene of SARS-CoV-2. Viruses from all three patients were found to be positive for the L452R mutation and negative for the N501Y mutation (data not shown), indicating that the patients were infected with the delta variant of SARS-CoV-2.

The results show that the saliva collected immediately after eating the tannin candy was negative for SARS-CoV- 2 as assessed by PCR (Fig. 4). The viral load in saliva then gradually increased over time, but it was still suppressed to approximately 1/1000 of that of the control even 60 min after finishing the tannin candy (Fig. 4). In contrast, saliva collected while eating the control candy did not exhibit such anti-viral effects.


First, we clearly demonstrated that persimmon-derived tannin inactivated the delta variant of SARS-CoV-2 in vitro. Such an antiviral effect against the delta variant, which has caused the most severe cases of COVID-19 compared with other known SARS-CoV- 2 variants, is highly beneficial.

The observed effect was dose- and time-dependent, and it was quite similar to the findings from our previous report using the non-variant and alpha variant SARS-CoV-2 [7]. Persimmon-derived tannin may inactivate SARS-CoV-2, regardless of the variant type. This feature of persimmon-derived tannin is completely different from vaccine and neutralizing antibody therapy, which have become less effective against SARS-CoV-2 variants such as delta and omicron [12,13], suggesting that persimmon-derived tannin could be effective even against new SARS-CoV-2 variants that may appear in the future. Persimmon-derived tannin has been reported to inactivate various viruses by forming large aggregates and inhibiting the viruses from binding to the host cells [6,7]; however, the mechanism of its antiviral effects is still unclear, and further investigation is necessary.

We also demonstrated that human saliva obtained from a volunteer while they were eating tannin-containing hard candy could inactivate SARS-CoV-2 and that eating tannin- containing hard candy reduced the viral load in the saliva of patients with COVID-19. The oral cavity and saliva play an important role in the transmission of COVID-19 via droplets and aerosols.

The salivary gland is also one of the main locations of virus replication, and a high viral load of SARS-CoV-2 is often detected in saliva [2]. Therefore, reducing the virus load in saliva may suppress the risk of disease transmission.

Saliva from healthy persons salivated while they were eating a tannin-containing candy significantly reduced the virus titers of SARS-CoV-2 by approximately 1/1000. Thus, persimmon-derived tannin has antiviral effects even when it is mixed with human saliva. In addition, our clinical examination revealed that saliva from patients with COVID-19 caused by the delta variant that was collected just after eating tannin-containing candy produced negative results when tested by SARS-CoV-2 PCR, and the virus inhibition effect lasted for at least 60 min.

COVID-19 is transmitted mainly by dispersed saliva. In our previous study [7] using a hamster model, the transmission of SARS-CoV-2 infection from infected hamsters to non-infected hamsters was suppressed by administering persimmon-derived tannin into the mouth of infected hamsters. Our current study supports the potential ability of persimmon-derived tannin in the mouth to inhibit COVID-19 transmission in humans.

We used a hard candy to administer persimmon-derived tannin into the mouth, even though mouthwashes were more often used for similar purposes in previous studies [14]. Hard candy is easily kept in the mouth for several minutes, which can allow the tannin to effectively inactivate the virus in the mouth.

Persimmon-derived tannin-containing candy can be used as a simple, safe, inexpensive, and immediately available method of COVID- 19 prophylaxis with the potential to be helpful in fighting against the ongoing COVID- 19 pandemic.

However, our study has several limitations. First, although the antiviral effect of tannin is dose-dependent, we did not assess the tannin concentration attained in the saliva while a tannin-containing candy is being consumed. It is difficult to fully assess the tannin in saliva because tannin binds to proteins in the oral cavity and also because the amount of saliva varies among individuals.

Second, only three patients with COVID-19 caused by the delta variant were included in our clinical examination because only hospitalized patients who had mild disease without complications were enrolled in the study, and because the delta variant was no longer as prevalent in Japan when study participants were enrolled. Available data from patients are limited. Third, this study is open-label test, and all participants ate control candy first and then tannin candy.

The order of the candy intake could have affected the results. Fourth, we performed plaque assays to assess the patient saliva samples, but visible plaques were not observed. The plaque assay we used may not be sensitive enough to detect virus infectivity when viral loads are low. A previous report similarly found that plaques could not be successfully observed from saliva samples, possibly because plaque formation was inhibited by saliva components [15].

In summary, we clearly demonstrate that persimmon-derived tannin has potential to inactivate the SARS-CoV-2 delta variant both in vitro and in vivo. Persimmon-derived tannin is a highly safe product extracted from a natural plant and may be a valuable candidate for COVID-19 protection regardless of the SARS-CoV-2 variant type.


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