COVID-19 Vaccinated Individuals Can Be a Source of SARS-CoV-2 Transmission—A Systematic Review

: Fundamental rights are probably given back earlier to COVID-19 vaccinated individuals assuming that they cannot spread SARS-CoV-2 anymore. The objective of the study was to determine if COVID-19 vaccinated individuals can still be the source of SARS-CoV-2 transmission. PubMed was searched for studies on 4 April 2021. All studies with original data on COVID-19 cases among vaccinated individuals (phase III RCTs) and on viral load in the upper respiratory tract of vaccinated macaques after a SARS-CoV-2 challenge were included. Symptomatic COVID-19 cases were found in four trials among vaccinated participants although less frequently than among control subjects. One study revealed asymptomatic COVID-19 cases in a similar frequency among 2.168 AZD1222-vaccinated subjects (1.0%) compared to 2.223 control subjects (1.0%). In 15 studies with vaccinated macaques, it was found that the load of SARS-CoV-2 RNA, subgenomic RNA and infectious virus in the upper respiratory tract is variable. Sterilizing immunity was found in none of the animal studies. Major limitations of the animal studies are that the SARS-CoV-2 challenge took place within a few weeks of the ﬁnal or only vaccine dose, that the viral challenge was often high and, in some studies, administered by up to four routes. Based on current knowledge it seems clear that COVID-19 vaccinated individuals can still be the source of SARS-CoV-2 transmission. vaccinated animals. Published peer-reviewed research articles and preprints were included. The effect of the vaccination on the incidence of COVID-19 cases (phase III RCTs) and on the viral load (genomic RNA, subgenomic RNA, infectious SARS-CoV-2) in the upper respiratory tract (nose or pharynx) of vaccinated macaques was extracted. This may allow the determination of whether SARS-CoV-2 transmission is still possible. The results are presented in tables and always compared to the control groups of non-vaccinated individuals or macaques.


Introduction
COVID-19 is spreading worldwide. In addition to many non-pharmaceutical measures [1], the vaccination against COVID-19 is regarded as a another element to reduce the probability of severe disease [2]. Many countries aim to reach a high proportion of vaccinated citizens. The German Minster of Justice, Christine Lambrecht, recently indicated that the restriction of fundamental rights during the COVID-19 pandemic can be taken back for vaccinated citizens when there is solid evidence that they cannot transmit SARS-CoV-2 anymore [3]. A similar vision was communicated by Jens Spahn, the Minister for Health in Germany. He indicated that individuals should be able visit shops without a rapid antigen test once they have completed a COVID-19 vaccination scheme [4]. That is why many people consider a vaccination for themselves with the aim to get fundamental rights back earlier. In addition, Dodd et al. have recently described that the two main motivations for COVID-19 vaccination are for individuals to protect themselves and others and to help to stop the virus spread [5]. This is the reason why quite a few healthcare workers consider a vaccination for themselves-to reduce the probability of severe COVID-19 and to prevent an unnoticed transmission of SARS-CoV-2 to their patients while being asymptomatic or presymptomatic. A similar motivation to avoid spreading the influenza virus among the general population has been described among medical residents in Italy for the influenza vaccination [6]. The aim of the review is therefore to find out if COVID-19 vaccinated individuals can still be the source of SARS-CoV-2 transmission irrespective of the presence of symptoms.

Materials and Methods
A Medline search was done on 4 April 2021 using the following terms: "COVID-19", "phase 3" and "vaccine" (63 hits), "COVID-19", "phase III" and "vaccine" (108 hits), and "COVID-19", "macaques" and "vaccine" (87 hits). All studies were screened by the author for original data for the frequency of symptomatic or asymptomatic COVID-19 cases among vaccinated individuals or macaques. In addition, the macaque studies were screened for original data on the viral load in the upper respiratory tract of vaccinated animals. Published peer-reviewed research articles and preprints were included. The effect of the vaccination on the incidence of COVID-19 cases (phase III RCTs) and on the viral load (genomic RNA, subgenomic RNA, infectious SARS-CoV-2) in the upper respiratory tract (nose or pharynx) of vaccinated macaques was extracted. This may allow the determination of whether SARS-CoV-2 transmission is still possible. The results are presented in tables and always compared to the control groups of non-vaccinated individuals or macaques.
Data were extracted from studies that describe COVID-19 cases among vaccinated individuals or macaques. In addition, viral load data were extracted from studies with vaccinated and artificially infected macaques ( Figure 1).

Materials and Methods
A Medline search was done on 4 April 2021 using the following terms: "COVID-19", "phase 3" and "vaccine" (63 hits), "COVID-19", "phase III" and "vaccine" (108 hits), and "COVID-19", "macaques" and "vaccine" (87 hits). All studies were screened by the author for original data for the frequency of symptomatic or asymptomatic COVID-19 cases among vaccinated individuals or macaques. In addition, the macaque studies were screened for original data on the viral load in the upper respiratory tract of vaccinated animals. Published peer-reviewed research articles and preprints were included. The effect of the vaccination on the incidence of COVID-19 cases (phase III RCTs) and on the viral load (genomic RNA, subgenomic RNA, infectious SARS-CoV-2) in the upper respiratory tract (nose or pharynx) of vaccinated macaques was extracted. This may allow the determination of whether SARS-CoV-2 transmission is still possible. The results are presented in tables and always compared to the control groups of non-vaccinated individuals or macaques.
Data were extracted from studies that describe COVID-19 cases among vaccinated individuals or macaques. In addition, viral load data were extracted from studies with vaccinated and artificially infected macaques ( Figure 1).

Symptomatic Vaccinated COVID-19 Cases as a Possible Source
Four phase III trials were found with original data on symptomatic COVID-19 cases among vaccinated and control subjects (Table 1). Symptomatic COVID-19 cases were found in each trial among vaccinated individuals although at a significantly lower proportion compared to the groups of control subjects. In addition, of a subgroup of 373 study participants vaccinated with standard dose of AZD1222, two of them were identified as symptomatic COVID-19 cases (0.5%) [7]. Based on these data it is clear that a small proportion of vaccinated individuals may still get COVID-19 and thereby be a possible source for viral spread. * The symptoms depend on the study: at least one of the following symptoms: fever ≥ 37.8 • C, cough, shortness of breath, anosmia or ageusia [7]; at least two of the following symptoms: fever (temperature ≥ 38 • C), chills, myalgia, headache, sore throat, or new olfactory or taste disorder, or as occurring in those who had at least one respiratory sign or symptom (including cough, shortness of breath, or clinical or radiographic evidence of pneumonia) [8]; at least one of the following symptoms: fever, new or increased cough, new or increased shortness of breath, chills, new or increased muscle pain, new loss of taste or smell, sore throat, diarrhea, or vomiting [9]; any clinical signs of a respiratory tract infection [10].
A recent analysis of COVID-19 infections among vaccinated and non-vaccinated healthcare workers revealed that 89.3% of COVID-19 infections were associated with symptoms with only 22.9% of them requiring medical attention whereas only 10.7% remained asymptomatic [11]. A total of 11 COVID-19 infections were noticed among the vaccinated healthcare workers, three of them were found more than 14 days after the second the second dose [11].

Asymptomatic Vaccinated COVID-19 Cases as a Possible Source
The same phase III trials were screened for information on the number of asymptomatic COVID-19 cases among vaccinated and control subjects. In the studies with BNT162b2 (BioNTech) and Sputnik V (Gamaleya), asymptomatic COVID-19 cases were not included in the analysis [9,10]. The results in the trial with mRNA 1273 (Moderna) on asymptomatic COVID-19 cases were described to be insufficient although some degree of prevention seemed to be possible [8]. The trial with AZD1222 (AstraZeneca) looked in addition at subjects with a positive SARS-CoV-2 RNA test result but without symptoms or with unknown symptoms. Among the 2.168 vaccinated seronegative subjects 22 were found as asymptomatic COVID-19 cases (1.0%), among the 2.223 seronegative control subjects 23 asymptomatic COVID-19 cases were detected (1.0%). In addition, of a subgroup of 373 seropositive study participants vaccinated with the standard dose of AZD1222, one of them was identified as an asymptomatic COVID-19 case (0.3%) [7].

Viral Clearance in Vaccinated and Artificially Infected Macaques
The efficacy of COVID-19 vaccines has also been studied in macaques because they develop an acute infection when challenged with SARS-CoV-2 [12][13][14][15]. The speed and extent of the viral clearance in the upper respiratory tract in vaccinated macaques may also indicate if they may spread SARS-CoV-2 despite vaccination.

Infectious SARS-CoV-2
Infectious SARS-CoV-2 can remain in the upper respiratory tract for a few days after a viral challenge although the number of animals with infectious viruses and the number of infectious viruses per sample were much lower in all four studies (Table 4). Table 3. Effect of COVID-19 vaccines and vaccine candidates on subgenomic RNA load (nose or throat) after a SARS-CoV-2 challenge in vaccinated and non-vaccinated macaques.

Discussion
Current evidence clearly shows that a small proportion of vaccinated individuals can still become a symptomatic COVID-19 case, even those individuals with a COVID-19 infection prior to vaccination (seropositive study participants) [16,17,25,27]. In addition, the phase III trial with AZD1222 provides evidence that the proportion of asymptomatic COVID-19 cases is equal in AZD1222-vaccinated and control subjects suggesting that viral clearance in the upper respiratory tract is more or less equal among vaccinated and control subjects. Vaccinated asymptomatic viral carriers may be more relevant for transmission because they do not even know or suspect that they may spread SARS-CoV-2.
All of the vaccines tested to date have conferred a substantial degree of protection to the immunized macaques although only a small number of animals was investigated in each study. That is why it is difficult to draw major conclusions without further study. In most macaques, there is no reasonable evidence for complete protection (i.e., "sterilizing immunity") within a few weeks after vaccination completion. The majority of studies provide evidence for remaining SARS-CoV-2 RNA in the upper respiratory tract after a viral challenge. Most studies described viral replication in the upper respiratory tract of vaccinated animals measuring subgenomic RNA. Few studies demonstrated that infectious SARS-CoV-2 can also remain in the upper respiratory tract for a few days after a viral challenge although the number of animals with infectious viruses and the number of infectious viruses per sample were much lower in all of the vaccinated compared to the control groups. Similar findings have been described in macaques which were artificially infected with SARS-CoV-2 and rechallenged with the virus after viral clearance [33].
Animal studies have major limitations. One of them is that the severity of COVID-19 disease is mostly mild in animals whereas severe disease can be seen in humans [34]. Nevertheless, SARS-CoV-2 can replicate rapidly in the upper airways of macaques and humans. That is why it can be assumed that the results on the nasal clearance of SARS-CoV-2 in macaques may indicate a similar reaction in the human upper airways. Another limitation is that the SARS-CoV-2 challenge was within a few weeks of the final or only vaccine dose. This is regarded as the time when the immune response is likely to be close to its peak. It is therefore unknown if the viral clearance in the upper respiratory tract would be as effective against challenges conducted many months after the immunization protocol has been completed [35]. It is likely that the immune response will gradually ease off so that the viral clearance in the upper respiratory tract might take longer or might be less effective. In this case vaccinated animals could possibly spread a higher viral load or could spread it for a longer period of time. The pattern may be similar in humans. A third limitation of the animal studies is that the viral challenge was often high and, in some studies, administered by up to four routes. As a general principle, it will be easier to protect against a low dose of a challenge virus than a higher one, all other things being equal.
The findings in the phase III trial with AZD1222 are supported by data obtained with macaques showing that the level of genomic and subgenomic RNA was similar in the upper respiratory tract of vaccinated and control animals. Only the load of infectious virus was partly reduced in AZD1222-vaccinated animals. Other vaccines reveal a faster and stronger clearance of SARS-CoV-2 RNA in the upper respiratory tract, some vaccines may even stop viral replication in the upper respiratory tract as suggested by a lack of subgenomic RNA. With this variety of results in mind it is clear that a sterilizing immunity cannot be achieved in all vaccinated individuals.
Vaccinated individuals can therefore not be ruled out as a possible source for SARS-CoV-2 transmission. In case of a COVID-19 infection in vaccinated individuals they will probably have a mild disease, maybe they remain asymptomatic. Based on these data it is possible that privileges for them may have an opposite effect because it seems to be more likely that they can be an asymptomatic viral spreader. Such a case has been reported recently in Halle, Germany [36]. Even when differentiating between the vaccinated and non-vaccinated is legal, it can still be unfair. Certifying those who are fit or vaccinated may stigmatize those who are not. There is ample historical evidence that tying advantage to fitness can amplify existing socioeconomic disparities. At the extreme, critics warn that excessive immunity advantages or vaccination certificates could create an Orwellian or dystopian social apartheid [37].
The assumption that vaccinated individuals cannot be a possible source of infection is not supported by current evidence. This finding may also have implications for healthcare workers and nursing staff in residential and nursing homes when the expectation towards a vaccination is to prevent them to be a possible source of transmission to patients or residents. If COVID-19 vaccines do not prevent transmission it also does not make sense to preferably return fundamental rights to vaccinated individuals. The focus of vaccination should be the individual protection against hospitalization, ICU, and death.

Conclusions
Based on current knowledge it seems clear that COVID-19 vaccinated individuals can still be the source of SARS-CoV-2 transmission. If COVID-19 vaccines do not prevent transmission it also does not make sense to preferably return fundamental rights to vaccinated individuals. The focus of vaccination should be the individual protection against hospitalization, ICU, and death. Conflicts of Interest: G.K. has received personal fees from Dr. Schumacher GmbH, Germany, for presentation and consultation.